Benzimisazo[4,5-f]isoquinolinone derivatives

ABSTRACT

Benzimidazo[4,5-f]isoquinolinone derivatives are inhibitors of Janus protein tyrosine kinases (Jak), and as such are useful as immunosuppressants, and in the treatment of diseases including asthma, allergies, autoimmune diseases.

BACKGROUND OF THE INVENTION

[0001] Janus protein tyrosine kinases (“Jak”s) associate with theintracellular portions of many cytokine and growth hormone receptors. AJak family protein kinase is characterized by seven regions of sequencehomology and four family members have been identified to date: Jak1,Jak2, Jak3 and Tyk2. Jak1, Jak2 and Tyk2 are expressed almostubiquitously whereas Jak3 appears to be expressed principally inhematopoietic cells. Jaks transduce extracellular signals byphosphorylating cytoplasmic proteins, among the best characterized ofwhich are the signal transducers and activators of transcription(“STAT”s). The STATs dimerize on phosphorylation and directly activatetranscription after nuclear translocation. These signaling eventsmediate such diverse biological outcomes as thymocyte development anderythrocyte differentiation.

[0002] Jak3 associates with the common gamma chain (γ_(c)) of theextracellular receptors for the following interleukins (IL's): IL-2,IL-4, IL-7, IL-9, IL-15. IL-4 is implicated in pathogenesis of asthmaand allergic inflammation. IL-4 signaling can be disrupted by blockingJak tyrosine kinase activity with the small molecule inhibitor AG490.Cells with genetic deficiencies in the Jaks show similar behavior:thymocytes derived from Jak1 deficient mice show an impairedresponsiveness to IL-4, and T cells from Jak3 deficient mice areunresponsive to IL-4. Taken together, these data support the hypothesisthat modulation of IL-4 signaling by modulation of Jak kinase activitywould be beneficial to patients suffering from allergic inflammation andasthma.

[0003] A Jak3 deficiency is associated with an immune compromised (SCID)phenotype in both rodents and humans. The SCID phenotype ofJak3-/-mammals and the lymphoid cell specific expression of Jak3 are twofavorable attributes of a target for an immune suppressant. The T cellsfrom Jak3 deficient mice did not respond to IL-2, and thymocytes derivedfrom Jak1 deficient mice showed impaired responses to IL-2. IL-2 has acentral role in regulation of T cells, and an antibody that binds to anextracellular portion of the IL-2 receptor is efficacious in preventingtransplant rejection. These data suggest that inhibitors of Jak proteinkinase in general and Jak3 protein kinase activity in particular couldimpede T-cell activation and prevent rejection of grafts followingtransplant surgery. Another use for these agents is to providetherapeutic benefit to patients suffering autoimmune disorders.

[0004] Constitutively active Jak2 has been found in the leukemic cellsof relapsing acute lymphoblastic leukemia patients, and treatment of theleukemic cells with AG490, a tyrosine kinase inhibitor, blocks both Jak2activity and proliferation. In addition, fusions of the Jak kinases andTEL proteins are transforming in Ba/F3 cells. Kinase inactive mutants ofJak1 introduced into bone marrow cells inhibit the ability of theoncogene v-Ab1 to activate STATs and to induce cytokine-independentproliferation. Hence inhibitors of Jak protein kinase activity may beused to treat neoplastic diseases such as leukemias.

[0005] Tyrosine kinase researchers have generated inhibitors in avariety of structural classes. Previous literature reports of Jak familyinhibitor scaffolds with efficacy in mouse disease models have includedbenzylidenemalonitriles (“tyrphostins”), quinazolines (WHI-P154, andWHI-P151), and pyrrolo[2,3-d]-pyrimidines. No dissociation constantsmeasured by steady state kinetic methods were reported for theseinhibitors but both the tyrphostins and WHI-P151 inhibit Jak drivenbiological events at micromolar concentrations.

SUMMARY OF THE INVENTION

[0006] The present invention relates to inhibitors of Janus proteintyrosine kinases useful as therapeutic agents, methods for theirpreparation and use, and pharmaceutical compositions containing suchcompounds.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention provides compounds of formula I:

[0008] wherein one of the

bond is a double bond, and the other is a single bond;

[0009] Q is N or C;

[0010] R¹ is attached to the nitrogen atom having the available valence,and is selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,aryl-C₁₋₃alkyl, and aryl wherein said alkyl, alkenyl, cycloalkyl, andaryl are optionally substituted with one to three groups independentlyselected from X;

[0011] R² is a group selected from R¹;

[0012] R³, R⁴, R⁶ and R⁷ are independently selected from hydrogen, X,C₂₋₆alkenyl and C₃₋₆cycloalkyl wherein said alkenyl and cycloalkyl areoptionally substituted with one to three groups independently selectedfrom X;

[0013] R⁵ is selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, Cy, andCy-C₁₋₃alkyl, wherein said alkyl, alkenyl, and Cy are optionallysubstituted with one to three groups independently selected from X;

[0014] Cy is selected from cycloalkyl, heterocyclyl, aryl, andheteroaryl;

[0015] X is selected from:

[0016] (a) halo,

[0017] (b) CN,

[0018] (c) OR^(a),

[0019] (d) C₁₋₆perfluoroalkyl,

[0020] (e) C(O)R^(a),

[0021] (f) C(O)OR^(a),

[0022] (g) C(O)NR^(b)R^(c),

[0023] (h) NR^(b)R^(c),

[0024] (i) NHR^(b)NHR^(b),

[0025] (j) NHC(O)R^(a),

[0026] (k) NHC(O)OR^(a),

[0027] (l) phenyl wherein phenyl is optionally substituted with one tothree groups independently selected from R^(x),

[0028] (m) C₁₋₆alkyl optionally substituted with OH, C₃₋₇cycloalkyl,phenyl, or heterocyclyl, wherein phenyl is optionally substituted withone to three groups independently selected from R^(x), and wherein saidheterocyclyl is optionally substituted with one to three groupsindependently selected from R^(y),

[0029] (n) heterocyclyl wherein said heterocyclyl is optionallysubstituted with one to three groups independently selected from R^(y),

[0030] (o) S(O)_(n)R^(a), wherein n is 0, 1 or 2; and

[0031] (p) SO₂NHR^(a);

[0032] R^(a), R^(b) and R^(c) are independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, Cy and Cy-C₁₋₃alkyl, wherein Cy isoptionally substituted with one to three groups selected from R^(y); or

[0033] R^(b) and R^(c) together with the atom(s) to which they areattached form a heterocyclic ring of 4 to 7 members containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(e);

[0034] R^(e) is selected from hydrogen, C₁₋₆alkyl, Cy and Cy-C₁₋₃alkyl;

[0035] R^(x) is selected from halo, phenyl, CN, NO₂, OH, OC₁₋₆alkyl,C₁₋₆alkyl, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, C(O)C₁₋₆alkyl,C(O)OC₁₋₆alkyl, C(O)NHC₁₋₆alkyl, C(O)N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆alkyl;

[0036] R^(y) is a group selected from R^(x), oxo, C₁₋₆alkyl substitutedwith C₃₋₇cycloalkyl, and C(O)OCH₂-phenyl;

[0037] or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment of formula I are compounds wherein R¹ isselected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl and aryl-C₁₋₃alkylwherein alkyl, cycloalkyl and aryl are optionally substituted with oneor two groups independently selected from X. Examples of R¹ include, butare not limited to, hydrogen, methyl, ethyl, dimethylaminoethyl,cyclopropyl and benzyl.

[0039] In another embodiment of formula I, R³ and R⁴ are independentlyselected from hydrogen, halogen and trifluoromethyl, and when Q is C andone or both of R³ and R⁴ are other than hydrogen, one of the substituentis attached to the 9-position (ring numbering as shown below). Examplesof R³/R⁴ include, but are not limited to, hydrogen/hydrogen;hydrogen/fluorine, chlorine, bromine or iodine; chlorine/chlorine;hydrogen/trifluoromethyl.

[0040] In another embodiment of formula I, R⁵ is selected from C₁₋₆alkyland Cy wherein each is optionally substituted with one to three groupsindependently selected from X. In one subset thereof, R⁵ is phenyloptionally substituted with one to three groups independently selectedfrom X. Examples or R⁵ include, but are not limited to, methyl, ethyl,n-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, 2- or 3- or 4-chlorophenyl, 2- or 3- or 4-fluorophenyl, 2- or 3-or 4-bromophenyl, 2- or 3- or 4-hydroxyphenyl, 2- or 3- or4-methylphenyl, 2- or 3- or 4-methoxyphenyl, 2- or 3- or4-trifluoromethylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2-fluoro-6-chlorophenyl,2-chloro-4-hydroxyphenyl, 2- or 3- or 4-pyridyl and 3-chloro-2-thienyl,and N-benzyloxycarbonyl-4-piperidyl.

[0041] In another embodiment of formula I, Q is C. Another embodiment offormula I are compounds wherein Q is N.

[0042] Representative compounds of formula I are as follows:

R¹ R² R³ R⁴ R⁵ H H 9-F H t-butyl H CH3 9-F H t-butyl 1-CH₃ H 9-F Ht-butyl 3-CH₃ H 9-F H t-butyl H H 9-F H Phenyl H H 9-F H 4-Cl-Ph H CH₃9-F H 4-Cl-Ph H H 9-F H 4-OCH₃-Ph H H 9-F H Methyl H H 9-F H 4-CH₃-Ph HH 9-F H 3-Cl-Ph H H 9-F H 2-CH₃-Ph H H 9-F H 2,6-diOCH₃-Ph H H 9-F H2-OCH₃-Ph H H 9-F H 2-Cl-Ph H H 9-F H 2-F-Ph H H 9-F H 2,6-diCl-Ph H H9-F H 2,6-diF-Ph H H 9-F H c-Hex H H 9-F H 2-F-6-Cl-Ph H H 9-F H 2-Br-PhH H 9-F H H H H 9-F H 2-OH-Ph H H 9-F H 3-OH-Ph H H 9-F H 4-OH-Ph H H9-F H 2-CF₃-Ph H H 9-F H 2-Cl-4-OH-Ph H H 9-F H c-Pen H H 9-F H n-propylH H 9-F H 3-Cl-2-thienyl H H 9-F H 3-pyridyl 1-CH₃ H 9-F H Phenyl1-CH₂CH₃ H 9-F H Phenyl 1-benzyl H 9-F H Phenyl 1-diCH₃-N- H 9-F HPhenyl ethyl 1-cPr H 9-F H Phenyl 1-CH₃ H 9-F H 2-CH₃-Ph 1-CH₃ H 9-F H2,6-diCl-Ph H H 9-Cl 10-Cl t-butyl H H 8-Cl 9-Cl t-butyl H H 9-Cl 10-Cl2,6-diCl-Ph H H 8-Cl 9-Cl 2,6-diCl-Ph H H 10-CF₃ H 1-CBZ-4-piperidyl* HH 10-CF₃ H 4-piperidyl H H H H t-butyl

[0043]

R¹ R² R³ R⁴ R⁵ H H H H t-butyl H CH3 H H t-butyl 1-CH₃ H H H t-butyl3-CH₃ H H H t-butyl H H H H Phenyl H H H H 4-Cl-Ph H CH₃ H H 4-Cl-Ph H HH H 4-OCH₃-Ph H H H H Methyl H H H H 4-CH₃-Ph H H H H 3-Cl-Ph H H H H2-CH₃-Ph H H H H 2,6-diOCH₃-Ph H H H H 2-OCH₃-Ph H H H H 2-Cl-Ph H H H H2-F-Ph H H H H 2,6-diCl-Ph H H H H 2,6-diP-Ph H H H H c-Hex H H H H2-F-6-Cl-Ph H H H H 2-Br-Ph H H H H H H H H H 2-OH-Ph H H H H 3-OH-Ph HH H H 4-OH-Ph H H H H 2-CF₃-Ph H H H H 2-Cl-4-OH-Ph H H H H c-Pen H H HH n-propyl H H H H 3-Cl-2-thienyl H H H H 3-pyridyl 1-CH₃ H H H Phenyl1-CH₂CH₃ H H H Phenyl 1-benzyl H H H Phenyl 1-diCH₃-N- H H H Phenylethyl 1-cPr H H H Phenyl 1-CH₃ H H H 2-CH₃-Ph 1-CH₃ H H H 2,6-diCl-Ph HH H 10-Cl t-butyl H H 8-Cl H t-butyl H H H 10-Cl 2,6-diCl-Ph H H 8-Cl H2,6-diCl-Ph H H H 10-CF₃ 4-piperidyl

[0044] “Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like.

[0045] “Alkenyl” means carbon chains which contain at least onecarbon-carbon double bond, and which may be linear or branched orcombinations thereof. Examples of alkenyl include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

[0046] “Alkynyl” means carbon chains which contain at least onecarbon-carbon triple bond, and which may be linear or branched orcombinations thereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

[0047] “Cycloalkyl” means mono- or bicyclic saturated carbocyclic rings,each of which having from 3 to 10 carbon atoms. The term also includesmonocyclic rings fused to an aryl group in which the point of attachmentis on the non-aromatic portion. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.

[0048] “Aryl” means mono- or bicyclic aromatic rings containing onlycarbon atoms. The term also includes aryl group fused to a monocycliccycloalkyl or monocyclic heterocyclyl group in which the point ofattachment is on the aromatic portion. Examples of aryl include phenyl,naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.

[0049] “Heteroaryl” means a mono- or bicyclic aromatic ring containingat least one heteroatom selected from N, O and S, with each ringcontaining 5 to 6 atoms. Examples of heteroaryl include pyrrolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl,thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl,triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.

[0050] “Heterocyclyl” means mono- or bicyclic saturated rings containingat least one heteroatom selected from N, S and O, each of said ringhaving from 3 to 10 atoms in which the point of attachment may be carbonor nitrogen. The term also includes monocyclic heterocycle fused to anaryl or heteroaryl group in which the point of attachment is on thenon-aromatic portion. Examples of “heterocyclyl” include pyrrolidinyl,piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl,benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl,dihydroindolyl, and the like. The term also includes partiallyunsaturated monocyclic rings that are not aromatic, such as 2- or4-pyridones attached through the nitrogen orN-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).

[0051] “Halogen” includes fluorine, chlorine, bromine and iodine.

[0052] Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

[0053] Compounds of Formula I may contain one or more asymmetric centersand can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

[0054] Some of the compounds described herein contain olefinic doublebonds, and unless specified otherwise, are meant to include both E and Zgeometric isomers.

[0055] Some of the compounds described herein may exist with differentpoints of attachment of hydrogen, referred to as tautomers. Such anexample may be a ketone and its enol form known as keto-enol tautomers.The individual tautomers as well as mixture thereof are encompassed withcompounds of Formula I.

[0056] Compounds of the Formula I may be separated intodiastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent, for example methanol or ethylacetate or a mixture thereof. The pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample by the use of an optically active acid as a resolving agent.

[0057] Alternatively, any enantiomer of a compound of the generalFormula I may be obtained by stereospecific synthesis using opticallypure starting materials or reagents of known configuration.

[0058] Salts

[0059] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases and inorganic or organic acids.Salts derived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

[0060] When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

[0061] It will be understood that, as used herein, references to thecompounds of Formula I are meant to also include the pharmaceuticallyacceptable salts.

[0062] Utilities

[0063] The ability of the compounds of Formula I to inhibit Jaksactivity, particularly Jak3 activity, makes them useful for preventingor reversing the symptoms, disorders or diseases induced by theactivation of Jaks, such as allergic disorders, asthma, autoimmune andother immune associated disorders; these compounds are also useful asimmunosuppressants to prevent transplant rejections. Allergic disordersinclude Type I immediate hypersensitivity reactions such as allergicrhinitis hay fever), allergic urticaria (hives), angioedema, allergicasthma and anaphylaxis, i.e., “anaphylactic shock.” Autoinmmune diseasesinclude systemic lupus erythematosis (SLE), myasthenia gravis, diabetes,rheumatoid arthritis, and Grave's disease. Compound of Formula I arealso useful for the treatment of neoplastic diseases such as leukemiasand lymphomas.

[0064] Dose Ranges

[0065] The magnitude of prophylactic or therapeutic dose of a compoundof Formula I will, of course, vary with the nature of the severity ofthe condition to be treated and with the particular compound of FormulaI and its route of administration. It will also vary according to theage, weight and response of the individual patient. In general, thedaily dose range lies within the range of from about 0.001 mg to about100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mgper kg, and most preferably 0.1 to 10 mg per kg, in single or divideddoses. On the other hand, it may be necessary to use dosages outsidethese limits in some cases.

[0066] For use where a composition for intravenous administration isemployed, a suitable dosage range is from about 0.001 mg to about 25 mg(preferably from 0.01 mg to about 1 mg) of a compound of Formula I perkg of body weight per day and for cytoprotective use from about 0.1 mgto about 100 mg (preferably from about 1 mg to about 100 mg and morepreferably from about 1 mg to about 10 mg) of a compound of Formula Iper kg of body weight per day.

[0067] In the case where an oral composition is employed, a suitabledosage range is, e.g. from about 0.01 mg to about 100 mg of a compoundof Formula I per kg of body weight per day, preferably from about 0.1 mgto about 10 mg per kg and for cytoprotective use from 0.1 mg to about100 mg (preferably from about 1 mg to about 100 mg and more preferablyfrom about 10 mg to about 100 mg) of a compound of Formula I per kg ofbody weight per day.

[0068] For the treatment of diseases of the eye, ophthalmic preparationsfor ocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

[0069] Pharmaceutical Compositions

[0070] Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

[0071] Any suitable route of administration may be employed forproviding a mammal, especially a human with an effective dosage of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.

[0072] The pharmaceutical compositions of the present invention comprisea compound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

[0073] The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

[0074] For administration by inhalation, the compounds of the presentinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or nebulisers. The compounds mayalso be delivered as powders which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. The preferred delivery systems for inhalation aremetered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of a compound of Formula I in suitablepropellants, such as fluorocarbons or hydrocarbons and dry powderinhalation (DPI) aerosol, which may be formulated as a dry powder of acompound of Formula I with or without additional excipients.

[0075] Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, ointments, lotions, dustingpowders, and the like.

[0076] In practical use, the compounds of Formula I can be combined asthe active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

[0077] In addition to the common dosage forms set out above, thecompounds of Formula I may also be administered by controlled releasemeans and/or delivery devices such as those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

[0078] Pharmaceutical compositions of the present invention suitable fororal administration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 1 mg to about500 mg of the active ingredient and each cachet or capsule contains fromabout 1 to about 500 mg of the active ingredient.

[0079] The following are examples of representative pharmaceuticaldosage forms for the compounds of Formula I: Injectable Suspension(I.M.) mg/mL Compound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection to atotal volume of 1 mL Tablet mg/tablet Compound of Formula I 25Microcrystalline Cellulose 415 Povidone 14.0 Pregelatinized Starch 43.5Magnesium Stearate 2.5 500 Capsule mg/capsule Compound of Formula I 25Lactose Powder 573.5 Magnesium Stearate 1.5 600 Aerosol Per canisterCompound of Formula I   24 mg Lecithin, NF Liq. Conc.  1.2 mgTrichlorofluoromethane, NF 4.025 g   Dichlorodifluoromethane, NF 12.15g  

[0080] Combination Therapy

[0081] Compounds of Formula I may be used in combination with otherdrugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds ofFormula I are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofFormula I is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients, in addition to a compound of Formula I. Examples ofother active ingredients that may be combined with a compound of FormulaI, either administered separately or in the same pharmaceuticalcompositions, include, but are not limited to: (a) antileukotrieneagents including, without limitation, leukotriene D4 receptorantagonists such as zafirlukast, montelukast, pranlukast, iralukast,pobilukast and SKB-106,203, and leukotriene biosynthesis inhibitors suchaszileuton and BAY-1005; (b) VLA-4 antagonists; (c) intranasal, inhaledand oral steroids such as beclomethasone, fluticasone, mometasone,flunisolide, budesonide, prednisolone, methylprednisolone,betamethasone, prednisone, dexamethasone, triamcinolone, andhydrocortisone; (d) immunosuppressants including calcineurin inhibitorssuch as cyclosporin and tacrolimus, rapamycin and other TOR proteininhibitors, purine biosynthesis inhibitors; (e) antihistamines(H1-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (f) beta agonistssuch as terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,bitolterol, salmeterol and pirbuterol; (g) other drugs for asthma andchronic obstructive pulmonary diseases such as theophylline, cromolynsodium, atropine, ipratropium bromide, and tiotropium bromide; (h)inhibitors of phosphodiesterase type IV (PDE-IV) such as cilomilast androflumilast; (i) antagonists of the chemokine receptors, especiallyCCR-1, CCR-2, and CCR-3; (j) PGD2 receptor antagonists; and (k)antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents.

[0082] The weight ratio of the compound of the Formula I to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.

[0083] Compounds of the present invention may be prepared by proceduresillustrated in the accompanying schemes.

[0084] Several methods for preparing the compounds in this invention areillustrated in the following Schemes and Examples. Starting materialsare made from known procedures or as illustrated.

[0085] Scheme 1 details the preparation of substituted ketoness 1-5which are intermediates in the synthesis of compounds of Formula I.Ketones 1-5 can be synthesized by reacting suitably substituted amides1-2 or readily available esters 1-3 with commercially available2-fluoro-4-methylpyridine 1-4 using a base such as sodiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithiumdiisopropylamide, n-butyllithium, sec-butyllithium, potassiumt-butoxide, and other suitable bases. N-methyl-N-methoxyamides 1-2 canbe prepared from commercially available acids 1-1 andN,O-dimethylhydroxylamine under standard coupling reaction conditions.

[0086] Scheme 2 details the preparation of substituted imidazoles 2-3,which are intermediates in the synthesis of compounds of Formula I.imidazoles 2-3 can be synthesized by condensation of2-hydroximino-ketones 2-2, or the corresponding 1,2-dione orα-bromoketone with an aldehyde and ammonium acetate in refluxing aceticacid. Hydroximinoketone 2-2 can be obtained by treatment of substitutedketone 2-1 with tert-butylnitrite in ethanol, methanol, isopropanol orother suitable solvents.

[0087] The preparation of benzo- or pyrido-fusedimidazo[4,5-ƒ]isoquinolin-7-one 3-3 is detailed in Scheme 3. SubstitutedN-hydroxyimidazole 3-1 can be treated with titanium trichloride or otherreducing agent, such as phosphorous trichloride, in methanol or othersuitable solvent such as chloroform, dichloromethane, ethanol,isopropanol, or tert-butanol at room temperature to afford substitutedimidazole 3-2. Upon UV irradiation of 3-2 in solvents such astetrahydrofuran, methanol, dichloromethane or the like substitutedbenzo- or pyrido-fused imidazo[4,5-ƒ]isoquinolin-7-one 3-3 can beobtained. Alternatively, benzo- or pyrido-fusedimidazo[4,5-ƒ]isoquinolin-7-ones 3-3 can be directly obtained fromsubstituted N-hydroxyimidazole 3-1 by UV irradiation of 3-1 in a solventsuch as tetrahydrofuran, methanol, dichloromethane or the like.

[0088] Scheme 4 illustrates the preparation of various N-substituted,derivatives of benzo- or pyrido-fused imidazo[4,5-f]isoquinolin-7-one4-1. Deprotonation of 4-1 with a base such as sodium hydride, lithiumdiisopropylamide, potassium hydride, lithium bis(trimethylsilyl)amide,sodium hydroxide, potassium hydroxide or the like followed by theaddition of an electrophile such as an alkyl halide, alkyl mesylate,alkyl tosylate, acyl halide, acid anhydride or the like, affords acompound of structure 4-2. Compound 4-2 can be further substituted bydeprotonation, followed by alkylation or acylation as described above toafford 4-3 and 4-4 as a separable mixture of isomers. Further, R² may beselectively removed to afford compounds of structures 4-5 and 4-6.

[0089] The two nitrogen atoms of the imidazole ring may be selectivelyand separately derivatized as described in Schemes 5 and 6.

[0090] In Scheme 5, the condensation of a hydroximinoketone 5-1 with analdehyde and a primary amine in refluxing acetic acid provides theN-oxo-imidazole 5-2. Upon reduction of N-oxo-imidazole 5-2 withphosphorous trichloride or other reagent such as titanium trichloride insolvents such as chloroform, dichloromethane, methanol, ethanol,isopropanol or the like, an N-substituted imidazole is obtained, whichupon UV irradiation in solvents such as tetrahydrofuran, methanol,dichloromethane or the like provides imidazo[4,5-ƒ]isoquinolin-7-one5-4.

[0091] In Scheme 6, an oxime of structure 6-1 can be reduced to thecorresponding amino alcohol 6-2 by hydrogenation over a suitablecatalyst such as palladium on carbon in an appropriate solvent such asmethanol, ethanol, ethyl acetate, THF or the like. Condensation of 6-2with an aldehyde under standard reducing conditions affords alkylamine6-3. Alternatively, amine 6-2 may be acylated and the resulting amidereduced to afford 6-3. Acylation of 6-3 with an acylating agent R⁵C(O)Xsuch as acid chloride, acid anhydride, or carboxylic acid in thepresence of a coupling reagent such as DCC, EDC or the like affordsamide 6-4. Oxidation of the alcohol to the ketone followed bycondensation with ammonium acetate in acetic acid affords thesubstituted imidazole 6-5, which upon UV irradiation in a solvent suchas tetrahydrofuran, methanol, dichloromethane or the like produces theimidazo[4,5-ƒ]isoquinolin-7-one 6-6.

[0092] Scheme 7 details the preparation ofpyrido-fused-imidazo[4,5-ƒ]isoquinolin-7-one 7-5. Tert-butyl4-methyl-2-pyridinylcarbamate 7-1 (Ihle, N. C.; Krause, A. E.; J. Org.Chem 1996, 61 (14), 4810-4811.) is deprotonated with butyl lithium andcondensed with ethyl isonicotinate to give ketone 7-2. Bromination withNBS followed by condensation with an amidine affords imidazoles 7-3.Cleavage of the tert-butyl carbamate with TFA followed by diazotizationand hydrolysis yields the pyridone substituted imidazoles 7-4.Pyrido-fused-imidazo[4,5-ƒ]isoquinolin-7-one 7-5 can then be obtainedupon UV irradiation of 7-4 in solvents such as tetrahydrofuran,methanol, dichloromethane or the like.

[0093] The following examples are provided to illustrate the inventionand are not to be construed as limiting the scope of the invention inany manner.

[0094] HPLC Conditions

[0095] LC 1. Retention time using the following conditions: Column: YMCODS A, 5 m, 4.6×50 mm; Gradient Eluent: 10:90 to 95:5 v/vacetonitrile/water+0.05% TFA over 4.5 min; Detection: PDA, 200-600 nm;Flow Rate: 2.5 mL/min.

[0096] LC 2. Retention time using the following conditions: Column: YMCPro-C18, 5 m, 4.6×50 mm; Gradient Eluent: 10:90 to 95:5 v/vacetonitrile/water+0.05% TFA over 3.0 min; Detection: PDA, 200-600 nm;Flow Rate: 2.5 mL/min.

EXAMPLE 12-tert-butyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0097]

[0098] Step A: 1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone

[0099] To a solution of sodium bis(trimethylsilyl)amide (0.465 L, 1M) inTBF (765 mL) under nitrogen, cooled to 2° C., was added2-fluoro-4-methylpyridine (25 g, 0.225 mol) and the solution stirred for45 minutes in an ice bath. Ethyl 4-fluoro-benzoate (35 mL, 0.239 mol)was added and the reaction was stirred for 1.5 hours at RT. The reactionmixture was poured into excess aqueous 2N HCl, and the aqueous layer wasmade basic with 5 N NaOH and extracted with EtOAc. The organic extractswere combined, washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂and filtered through a cotton plug. Hexanes were added and the CH₂Cl₂was removed under reduced pressure until precipitation of the titlecompound occurred as a pale yellow solid (43.2 g).

[0100]¹H NMR (CDCl₃, 500 MHz): δ 8.19 (brs, 1H), 8.04 (s, 2H), 7.19 (m,2H), 7.09 (s, 1H), 6.86 (s, 1H), 4.32 (s, 2H). MS(ES) 234.2 (M+1); LC 1:2.81 min.

[0101] Step B:1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime

[0102] To a solution of1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone (43 g, 0.184 mol) inethanol (800 mL) at −10° C. was added dropwise t-butylnitrite (24.1 mL,0.20 mol) over 10 minutes followed by 2.5 M HCl in absolute ethanol (60mL, 0.15 mol). The reaction temperature was maintained at −5° C. duringthese additions. After addition was complete, the dry ice bath wasremoved and the reaction was allowed to warm to RT and stirredovernight. The ethanol was removed under reduced pressure and theresidue was diluted with H₂O and made basic with saturated NaHCO₃. Itwas extracted with EtOAc, the combined organic extracts were washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude residue was taken up in methanol/isopropanol and mixed withtoluene. The methanol/isopropanol mixture was concentrated under reducedpressure and the title compound was recrystallized from hexane/toluene(47.5 g).

[0103]¹H NMR (CD₃OD, 500 MHz): δ 7.95-8.27 (m, 3H), 7.10-7.47 (m, 4H).MS(ES) 263.1 (M+1); LC 1: 2.83 min.

[0104] Step C:4-[2-tert-butyl-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0105] To a solution of1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(47.3 g, 0.18 mol) in acetic acid (1 L) under nitrogen was addedtrimethylacetaldehyde (21.6 mL, 0.19 mol) followed by ammonium acetate(277.5 g, 3.6 mol) and then it was heated to reflux for three hours. Theacetic acid was removed under reduced pressure and the remainingmaterial was taken up in water. The pH of the solution was adjusted to8-10 by addition of solid ammonium hydroxide and was extracted withEtOAc. The solvent was removed under reduced pressure and the crudeproduct was dissolved in methanol with sufficient ethanol added toeffect dissolution. The solvent was removed under reduced pressure; theproduct was twice dissolved in ethanol and concentrated to a smallvolume under reduced pressure to azeotropically remove water. The titlecompound was recrystallized from ethanol and hexane (28.8 g).

[0106]¹H NMR (DMSO-d₆, 500 MHz): δ 11.55 (s, 1H), 11.34 (s, 1H), 7.45(m, 2H), 7.32 (s, 1H), 7.09 (m, 2H), 6.41 (br s, 1H), 6.02 (br s, 1H),1.37 (s, 9H). MS(ES) 328.1 (M+1)); LC1: 1.57 min.

[0107] Step D:4-[2-tert-butyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0108] To a solution of4-[2-tert-butyl-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one(28 g, 0.086 mol) in methanol (1 L) at 0° C. under nitrogen was addedTiCl₃ (10% w/w in 20% w/w HCl, 450 ml) over 45 minutes while maintainingthe reaction temperature under 10° C. The solution was warmed to RT andstirred overnight. The methanol was removed under reduced pressure andthe solution was made basic with saturated NaHCO₃ and 5 N NaOH. Ethylacetate was added and it was stirred for 4 hours. The solution wasfiltered through a Solka floc pad to remove the solids. The filtrate wasextracted with EtOAc and the organic layer was then washed twice withbrine, dried over Na₂SO₄ and concentrated to dryness to yield crudeproduct. It was purified by flash chromatography using CH₂Cl₂/2%-10%methanol as an eluant to yield the title compound as a mixture ofimidazole tautomers.

[0109]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer: δ 12.05 (s, 1H);11.25 (br s, 1H); 7.47 (m, 2H); 7.28 (m, 2H); 7.17 (m, 1H); 6.32 (d,J=1.4 Hz, 1H); 6.23 (dd, J₁=6.8 Hz, J₂=1.8 Hz, 1H); 1.33 (s, 9H). MS(ES)312.2 (M+1)); LC 1: 1.49 min.

[0110] Step E:2-tet-butyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0111] To4-[2-tert-butyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one(2.0 g, 6.4 mmol) in a Pyrex vessel was added TBF (2 L) and the solutionwas irradiated with stirring with light >350 nm for 45 minutes. Duringirradiation, the solution transiently turned a reddish pink; the colordisappeared on further stirring without irradiation. At this juncture,further irradiation did not reinitiate the reaction. Two more batcheswere treated identically. The solvent was removed under reducedpressure. The crude material was purified by flash chromatography onsilica gel using TBF/toluene (3/7→7/3) as an eluant. The title compound(2.6 g) was obtained as a mixture of imidazole tautomers followingrecrystallization from methanol.

[0112]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer: δ 12.84 (s, 1H);11.59 (s, 1H); 10.05 (m, 1H); 8.55 (m, 1H); 7.60 (m, 1H); 7.51 (br s,1H); 7.25 (br s, 1H); 3.32 (s, 9H). MS(ES) 310.2 (M+1); LC 1: 1.81 min.

EXAMPLE 22-tert-butyl-9-fluoro-6-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0113]

[0114] To a stirred solution of2-tert-butyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(40 mg, 0.129 mmol) in dry DMF (1.5 mL) at 0° C. was added NaH (60 wt.%) (6 mg, 0.15 mmol). After stirring for 5 minutes, iodomethane (9 μL,0.142 mmol) was added, and the reaction mixture was slowly warmed toroom temperature over 2 h. The mixture was cooled in ice bath and thereaction was quenched with water. The reaction mixture was diluted withEtOAc, washed with water followed by brine, then dried over Na₂SO₄.After removal of the solvent the crude was purified by preparative thinlayer chromatography (1:9 MeOH:CH₂Cl₂ as eluent) to obtain the titlecompound as a mixture of imidazole tautomers.

[0115]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer: δ 12.9 (s, 1H);10.08 (dd, J₁=14.2 Hz, J₂=2.7 Hz, 1H); 8.6 (dd, J₁=8.8 Hz, J₂=6.6 Hz,1H); 7.89 (d, J=7.1 Hz, 1H); 7.6 (dt, J₁=8.7 Hz, J₂=2.8 Hz, 1H); 7.28(d, J=7.1 Hz, 1H); 3.64 (s, 3H); 1.5 (s, 9H). MS(ES) 324 (M+1); LC 1:1.46 min.

EXAMPLE 32-tert-butyl-9-fluoro-1-methyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-oneand2-tert-butyl-9-fluoro-3-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0116]

[0117] Step A:2-tert-butyl-9-fluoro-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0118] The title compound was prepared according to the proceduredescribed in EXAMPLE 2 using 2-(trimethylsilyl)ethoxymethyl chloride

[0119] MS(ES) 440 (M+1); LC 1: 2.26 min.

[0120] Step B:2-tert-butyl-9-fluoro-1-methyl-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer A)2-tert-butyl-9-fluoro-3-methyl-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer B)

[0121] The title compounds were prepared as regioisomers and separatedaccording to the procedure described in EXAMPLE 2.

[0122] Isomer A: ¹H NMR (CDCl₃, 500 MHz): δ 10.29 (dd, J=2.7, 13.7 Hz,1H); 8.42 (dd, J=6.0, 9.2 Hz, 1H); 7.60 (d, J=7.4 Hz, 1H); 7.55 (d,J=7.4 Hz, 1H); 7.38 (m, 1H); 5.59 (s, 2H); 4.38 (s, 3H); 3.70 (dd,J₁=J₂=8.2 Hz, 2H); 1.65 (s, 9H); 0.98 (dd, J₁=J₂=8.2 Hz, 2H); −0.02 (s,9H).

[0123] Isomer B: ¹H NMR (CDCl₃, 500 MHz): δ 10.01 (dd, J₁=14.2, J₂=2.5Hz, 1H); 8.73 (dd, J₁=8.9, J₂=6.5 Hz, 1H); 7.52 (d, J=7.5 Hz, 1H); 7.42(m, 1H); 7.22 (d, J=7.5 Hz, 1H); 5.57 (s, 2H); 4.32 (s, 3H); 3.71 (dd,J₁=J₂=8.2 Hz, 2H); 1.66 (s, 9H); 0.99 (dd, J₁=J₂=8.2 Hz, 2H); 0.0 (s,9H).

[0124] Step C:2-tert-butyl-9-fluoro-1-methyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-oneand2-tert-butyl-9-fluoro-3-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0125] To a solution of2-tert-butyl-9-fluoro-1-methyl-6-{[2-(trimethylsilyl)-ethoxy]methyl}-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer A) (17 mg, 0.037 mmol) in THF (1.0 mL) was addedtetrabutylammonium fluoride (75 μL, 1.0 M in THF) at room temperature,then it was heated at 60° C. for 3 h. The solvent was removed in vacuo,and the crude residue was purified by preparative thin layerchromatography (5% MeOH/CH₂Cl₂ as an eluent) to obtain the titlecompound.

[0126]¹H NMR (DMSO-d₆, 500 MHz): δ 11.65 (brs, 1H); 10.25 (dd, J₁=14.2Hz, J₂=2.9 Hz, 1H); 8.65 (dd, J₁=9.0 Hz, J₂=6.0 Hz, 1H); 7.56 (m, 1H);7.54 (d, J=6.6 Hz, 1H); 7.30 (d, J=6.6 Hz, 1H); 4.38 (s, 3H); 1.56 (s,9H). MS(ES) 324 (M+1); LC 1: 1.55 min.

[0127] Similarly, starting from isomer B of Step B,2-tert-butyl-9-fluoro-3-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-onewas prepared.

[0128]¹H NMR (DMSO-d₆, 500 MHz): δ 11.81 (brs, 1H); 10.05 (dd, J₁=14.4Hz, J₂=2.7 Hz, 1H); 8.58 (dd, J₁=8.9 Hz, J₂=6.6 Hz, 1H); 7.57 (d, J=7.4Hz, 1H); 7.52 (m, 1H); 7.37 (d, J=7.4 Hz, 1H); 4.32 (s, 3H); 1.58 (s,9H). MS(ES) 324 (M+1); LC 1: 1.46 min.

EXAMPLE 49-fluoro-2-phenyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0129]

[0130] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-phenyl-1H-imidazol-5-yl]pyridin-2(1H)-one

[0131] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoro-pyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with benzaldehyde).

[0132] Mass spectrum (LC-MS, ES+): 348.1 (M+1), LC 1: 1.30 min. ¹H NMR(CD₃OD, 500 MHz): δ 8.12 (d, J=7.3 Hz, 2H); 7.56-7.44 (aromatic Hs, 5H);7.41 (d, J=6.6 Hz, 1H); 7.14 (d, J=8.9 Hz, 1H); 7.13 (d, J=8.7 Hz, 1H);6.73 (d, J=1.3 Hz, 1H); 6.47 (dd, J₁=6.6 Hz, J₂=1.6 Hz, 1H).

[0133] Step B:4-[4-(4-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]pyridin-2(1H)-one

[0134] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-phenyl-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step D.

[0135] Mass spectrum (LC-MS, ES+): 332.1 (M+1), LC 1: 1.18 min. ¹H NMR(CDCl₃, 500 Hz): δ 8.00 (d, J=7.6 Hz, 2H); 7.54-7.35 (aromatic Hs, 5H);7.14 (d, J=6.8 Hz, 1H); 7.09 (d, J=8.7 Hz, 1H); 7.07. (d, J=8.7 Hz, 1H);6.75 (d, J=1.6 Hz, 1H); 6.36 (brs, 1H).

[0136] Step C:9-fluoro-2-phenyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0137] The title compound was prepared from4-[4-(4-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]pyridin-2(1H)-one ofStep B following the procedure described in EXAMPLE 1, Step E.

[0138] Mass spectrum (LC-MS, ES+): 330.1 (M+1), LC 1: 1.56 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 10.05 (brd, 1H); 8.65 (dd, J₁=8.7 Hz, J₂=6.4 Hz,1H); 8.31 (d, J=7.6 Hz, 2H); 7.66-7.48 (aromatic Hs, 5H); 7.37 (d, J=6.7Hz, 1H).

EXAMPLE 52-(4-chlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0139]

[0140] Step A:4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0141] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoro-pyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 4-chlorobenzaldehyde).

[0142] Mass spectrum (LC-MS, ES+): 382.1 (M+1), LC 1: 1.63 min. ¹H NMR(CD₃OD, 500 MHz): δ 8.23 (d, J=8.7 Hz, 2H); 7.50-7.38 (aromatic Hs, 4H);7.32 (d, J=6.9 Hz, 1H); 7.09 (d, J=8.9 Hz, 1H); 7.07 (d, J=8.7 Hz, 1H);6.74 (s, 1H); 6.58 (d, J=6.9 Hz, 1H).

[0143] Step B:4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0144] The title compound was prepared from4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step D.

[0145] Mass spectrum (LC-MS, ES+): 366.1 (+1), LC 1: 1.48 min. ¹H NMR(CD₃OD, 500 MHz): δ 7.98 (d, J=8.5 Hz, 2H); 7.58-7.47 (m, 4H); 7.36 (d,J=6.6 Hz, 1H); 7.22 (t, 2H); 6.71 (s, 1H); 6.55 (brs, 1H).

[0146] Step C:2-(4-chlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0147] The title compound was prepared from4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step B following the procedure described in EXAMPLE 1, Step E.

[0148] Mass spectrum (LC-MS, ES+): 364.1 (M+1), LC 1: 2.04 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 10.05 (d, J=13.7 Hz, 1H); 8.64 (dd, J₁=8.9 Hz,J₂=6.4 Hz, 1H); 8.32 (d, J=8.5 Hz, 2H); 7.69 (d, J=8.5 Hz, 2H); 7.63(brs, 2H); 7.35 (d, J=6.8 Hz, 1H).

EXAMPLE 62-(4-chlorophenyl)-9-fluoro-6-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0149]

[0150] Step A:4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-methoxy-1H-imidazol-5-yl]-1-methylpyridin-2(1H)-one

[0151] The title compound was prepared from4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneEXAMPLE 5, Step A) following the procedure described in EXAMPLE 2 (2.4eq. of iodomethane was used).

[0152] Mass spectrum (LC-MS, ES+): 410.1 (M+1), LC 1: 3.19 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 8.08 (d, J=8.7 Hz, 2H); 7.78 (d, J=6.9 Hz, 1H);7.62 (d, J=8.7 Hz, 2H); 7.58 (d, J=8.7 Hz, 1H); 7.57 (d, J=8.7 Hz, 1H);7.22 (d, J=8.9 Hz, 1H); 7.20 (d, J=8.7 Hz, 1H); 6.56 (d, J=1.8 Hz, 1H);6.22 (dd, J₁=6.9 Hz, J₂=1.8 Hz, 1H).

[0153] Step B:2-(4-chlorophenyl)-9-fluoro-6-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0154] The title compound was prepared from4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-methoxy-1H-imidazol-5-yl]-1-methylpyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0155] Mass spectrum (LC-MS, ES+): 378.1 (M+1), LC 1: 2.24 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 10.06 (brd, 1H); 8.65 (d, J₁=8.7 Hz, J₂=6.4 Hz,1H); 8.32 (d, J=8.2 Hz, 2H); 8.0 (brs, 1H); 7.70 (d, J=8.5 Hz, 2H); 7.63(brs, 1H); 7.37 (d, J=7.1 Hz, 1H).

EXAMPLE 79-fluoro-2-(4-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0156]

[0157] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(4-methoxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0158] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoro-pyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 4-methoxybenzaldehyde).

[0159] Mass spectrum (LC-MS, ES+): 378.2 (M+1), LC 1: 1.34 min.

[0160] Step B:9-fluoro-2-(4-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0161] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(4-methoxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0162] Mass spectrum (LC-MS, ES+): 360.2 (M+1), LC 1: 1.55 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.7 (brs, 1H); 10.05 (brs, 1H); 8.63 (dd, J₁=8.9Hz, J₂=6.4 Hz, 1H); 8.24 (brs, 2H); 7.60 (brd, 3H); 7.35 (d, J=6.9 Hz,1H); 7.16 (d, J=8.7 Hz, 2H).

EXAMPLE 89-fluoro-2-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0163]

[0164] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-methyl-1H-imidazol-5-yl]pyridin-2(1H)-one

[0165] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoro-pyridin-4-yl)ethane-1,2-dione 2-oximeEXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-methyl-1,3-dioxolane).

[0166] Mass spectrum (LC-MS, ES+): 286.0 (M+1), LC 1: 0.86 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 7.45 (m, 2H); 7.31 (d, J=6.6 Hz, 1H); 7.23 (t,1H); 7.18-7.10 (m, 2H); 6.38 (s, 1H); 6.02 (d, J=6.8 Hz, 1H).

[0167] Step B:9-fluoro-2-methyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0168] The title compound was prepared as a mixture of imidazoletautomers from4-[4-(4-fluorophenyl)-1-hydroxy-2-methyl-1H-imidazol-5-yl]pyridin-2(1H)-one(EXAMPLE 8, Step A) following the procedure described in EXAMPLE 1, StepE.

[0169] Mass spectrum (LC-MS, ES+): 268.1 (M+1), LC 1: 1.44 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 13.25 (brd, 1H); 10.04 (brd,1H); 8.50 (brs, 1H); 7.58 (brs, 2H); 7.22 (m, 1H); 6.65 (brs, 1H); 2.60(s, 3H).

EXAMPLE 99-fluoro-2-(4-methylphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0170]

[0171] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(4-methylphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0172] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 4-methylbenzaldehyde).

[0173] Mass spectrum (LC-MS, ES+): 362.1 (M+1), LC 1: 1.41 min. ¹H NMRDMSO-d₆, 500 MHz): δ 7.96 (d, J=8.0 Hz, 2H); 7.56-7.12 (aromatic Hs,7H); 6.45 (s, 1H); 6.09(d, J=7.1 Hz, 1H).

[0174] Step B:9-fluoro-2-(4-methylphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0175] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(4-methylphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0176] Mass spectrum (LC-MS, ES+): 344.1 (M+1), LC 1: 1.70 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 11.7 (brs, 1H); 10.02 (dd,1H); 8.63 (m, 1H); 8.18 (d, J=8.2 Hz, 2H); 7.658 (m, 2H); 7.41 (d, J=8.3Hz, 2H); 7.34 (s, 1H); 2.40 (s, 3H).

EXAMPLE 102-(3-chlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0177]

[0178] Step A:4-[2-(3-chlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0179] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 3-chlorobenzaldehyde).

[0180] Mass spectrum (LC-MS, ES+): 382.2 (M+1), LC 1: 1.70 min.

[0181] Step B:2-(3-chlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0182] The title compound was prepared from4-[2-(3-chlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0183] Mass spectrum (LC-MS, ES+): 364.0 (M+1), LC 1: 2.12 min.

EXAMPLE 119-fluoro-2-(2-methylphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0184]

[0185] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(2-methylphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0186] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-methylbenzaldehyde).

[0187] Mass spectrum (LC-MS, ES+): 362.1 (M+1), LC 1: 1.31 min.

[0188] Step B:4-[4-(4-fluorophenyl)-2-(2-methylphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0189] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(2-methylphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step D.

[0190] Mass spectrum (LC-MS, ES+): 346.1 (M+1), LC 1: 1.21 min.

[0191] Step C:9-fluoro-2-(2-methylphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0192] The title compound was prepared from4-[4-(4-fluorophenyl)-2-(2-methylphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step B following the procedure described in EXAMPLE 1, Step E.

[0193] Mass spectrum (LC-MS, ES+): 344.1 (M+1), LC 1: 1.58 min.

EXAMPLE 122-(2,6-dimethoxyphenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0194]

[0195] Step A:4-[2-(2,6-dimethoxyphenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0196] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2,6-dimethoxybenzaldehyde).

[0197] Mass spectrum (LC-MS, ES+): 408.2 (M+1), LC 1: 1.24 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.6 (brs, 1H); 7.54-7.12 (aromatic Hs, 6H); 6.74(d, J=8.5 Hz, 2H); 6.47 (s, 1H); 6.07 (d, J=6.8 Hz, 1H); 3.70 (s, 6H).

[0198] Step B:2-(2,6-dimethoxyphenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0199] The title compound was prepared from4-[2-(2,6-dimethoxyphenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0200] Mass spectrum (LC-MS, ES+): 390.2 (M+1), LC 1: 2.01 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 13.40 (s, 1H); 11.64 (s,1H); 10.08 (d, J=12.4 Hz, 1H); 8.38 (m, 1H); 7.55 (m, 3H); 7.25 (d,J=6.8 Hz, 1H); 6.47 (s, 1H); 6.84 (d, J=8.3 Hz, 2H); 3.71 (s, 6H).

EXAMPLE 139-fluoro-2-(2-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0201]

[0202] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(2-methoxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0203] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-methoxybenzaldehyde).

[0204] Mass spectrum (LC-MS, ES+): 378.2 (M+1), LC 1: 1.74 min. Partial¹H NMR (DMSO-d₆, 500 MHz): δ 3.79 (s, 3H).

[0205] Step B:9-fluoro-2-(2-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0206] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(2-methoxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0207] Mass spectrum (LC-MS, ES+): 360.1 (M+1), LC 1: 1.62 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 12.98 (s, 1H); 11.75 (s,1H); 10.08, (dd, J₁=14.4 Hz, J₂=2.5 Hz, 1H); 8.77 (dd, J₁=8.5 Hz, J₂=6.2Hz, 1H); 7.60 (m, 3H); 7.27 (d, J=8.3 Hz, 2H); 7.16 (m, 1H); 4.00 (s,3H).

EXAMPLE 142-(2-chlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0208]

[0209] Step A:2-(2-Chlorophenyl)-5-(4-fluorophenyl)-3-N-hydroxy-4-(pyridon-3-yl)-imidazole

[0210] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oximeEXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-chlorobenzaldehyde).

[0211] Mass spectrum (LC-MS, ES+): 382.2 (M+1), LC 1: 1.42 min.

[0212] Step B:2-(2-chlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0213] The title compound was prepared from2-(2-chlorophenyl)-5-(4-fluoro-phenyl)-3-N-hydroxy-4-(pyridon-3-yl)-imidazoleof Step A following the procedure described in EXAMPLE 1, Step E.

[0214] Mass spectrum (LC-MS, ES+): 364.1 (M+1), LC 1: 1.75 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.72 (brs, 1H); 10.06 (brd, J=11.9 Hz, 1H); 8.56(brs, 1H); 7.89 (dd, J₁=7.6 Hz, J₂=1.7 Hz, 1H); 7.70 (d, J=7.3 Hz, 1H);7.59 (m, 5H); 7.29 (brs, 1H).

EXAMPLE 159-fluoro-2-(2-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0215]

[0216] Step A:4-[2-(2-fluorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0217] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-fluorobenzaldehyde).

[0218] Mass spectrum (LC-MS, ES+): 350.2 (M+1).

[0219] Step B:9-fluoro-2-(2-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0220] The title compound was prepared from4-[2-(2-fluorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0221] Mass spectrum (LC-MS, ES+): 348.0 (M+1), LC 1: 1.78 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.72 (brs, 1H); 10.06 (brs, 1H); 8.70 (brs, 1H);8.17 (t, J=7.3 Hz, 1H); 7.60 (m, 2H); 7.52-7.20 (m, 3H); 6.65 (brs, 2H).

EXAMPLE 162-(2,6-dichlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0222]

[0223] Step A:4-[2-(2,6-dichlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0224] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2,6-dichlorobenzaldehyde).

[0225] Mass spectrum (LC-MS, ES+): 416.1 (M+1), LC 1: 1.62 min.

[0226] Step B:2-(2,6-dichlorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0227] The title compound was prepared from4-[2-(2,6-dichlorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0228] Mass spectrum (LC-MS, ES+): 398.2 (M+1), LC 1: 1.86 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 11.72 (brs, 1H); 10.10 (brd,J=12.1 Hz, 1H); 8.58 (brs, 1H); 7.76-7.54 (m, 5H); 7.27 (brs, 1H).

EXAMPLE 172-(2,6-difluorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0229]

[0230] Step A:4-[2-(2,6-difluorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0231] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2,6-difluorobenzaldehyde).

[0232] Mass spectrum (LC-MS, ES+): 384.2 (N+1), LC 1: 1.48 min.

[0233] Step B:2-(2,6-difluorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0234] The title compound was prepared from4-[2-(2,6-difluorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0235] Mass spectrum (LC-MS, ES+): 366.1 (M+1), LC 1: 1.72 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 11.72 (brs, 1H); 10.10 (brd,J=12.4 Hz, 1H); 8.50 (brs, 1H); 7.70 (m, 1H); 7.60 (brs, 3H); 7.39 (t,J=8.2 Hz, 2H); 7.30 (brs, 1H).

EXAMPLE 182-cyclohexyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0236]

[0237] Step A:4-[2-cyclohexyl-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0238] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with cyclohexanecarboxaldehyde).

[0239] Mass spectrum (LC-MS, ES+): 354.1 (M+1), LC 1: 1.31 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.50 (brs, 1H); 7.45 (m, 2H); 7.32 (brd, J=5.4Hz, 1H); 7.14 (d, J=8.9 Hz, 1H); 7.12 (d, J=8.7 Hz, 1H); 6.39 (s, 1H);6.01 (d, J=6.2 Hz, 1H); 2.82 (brs, 1H); 1.88 (m, 2H); 1.77 (m, 2H); 1.66(m, 1H); 1.53 (m, 2H); 1.38-1.20 (m, 4H).

[0240] Step B:2-cyclohexyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0241] The title compound was prepared from4-[2-cyclohexyl-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0242] Mass spectrum (LC-MS, ES+): 336.1 (M+1), LC 1: 1.44 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 13.08 (brs, 1H); 11.60 (brs, 1H); 10.00 (brs, 1H);8.45 (brs, 1H); 7.55 (brs, 2H); 7.20 (brs, 1H); 2.98 (t, J=11.2 Hz, 1H);2.10 (d, J=3.9 Hz, 1H); 1.85 (m, 2H); 1.72 (m, 3H); 1.50-1.16 (m, 4H).

EXAMPLE 192-(2-chloro-6-fluorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0243]

[0244] Step A:4-[2-(2-chloro-6-fluorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0245] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-chloro-6-fluorobenzaldehyde).

[0246] Mass spectrum (LC-MS, ES+): 400.2 (M+1), RT: 1.56 min.

[0247] Step B:2-(2-chloro-6-fluorophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0248] The title compound was prepared from4-[2-(2-chloro-6-fluorophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0249] Mass spectrum (LC-MS, ES+): 382.1 (M+1), LC 1: 1.80 min.

EXAMPLE 202-(2-bromophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0250]

[0251] Step A:4-[2-(2-bromophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0252] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-bromobenzaldehyde).

[0253] Mass spectrum (LC-MS, ES+): 426.1 (M+1), LC 1: 1.45 min.

[0254] Step B:2-(2-bromophenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0255] The title compound was prepared from4-[2-(2-bromophenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0256] Mass spectrum (LC-MS, ES+): 408.1 (M+1), LC 1: 1.76 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.72 (brs, 1H); 10.05 (brs, 1H); 8.52 (brs, 1H);7.87 (dd, J₁=8.2 Hz, J₂=1.2 Hz, 1H); 7.81 (dd, J₁=7.8 Hz, J₂=1.1 Hz,1H); 7.60 (dt, J₁=7.5 Hz, J₂=1.1 Hz, 4H); 7.51 (dt, J₁=7.5 Hz, J₂=1.6Hz, 1H); 7.27 (brs, 1H).

EXAMPLE 219-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0257]

[0258] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0259] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with formaldehyde).

[0260] Mass spectrum (LC-MS, ES+): 255.9 (M+1), LC 1: 0.75 min.

[0261] Step B:9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0262] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one ofStep A following the procedure described in EXAMPLE 1, Step E.

[0263] Mass spectrum (LC-MS, ES+): 253.9 (M+1), LC 1: 1.09 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.70 (brs, 1H); 10.04 (d, J=13.0 Hz, 1H); 8.48(brs, 1H); 8.44 (s, 1H); 7.58 (m, 2H); 7.24 (brs, 1H).

EXAMPLE 229-fluoro-2-(2-hydroxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0264]

[0265] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(2-hydroxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0266] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-hydroxybenzaldehyde).

[0267] Mass spectrum (LC-MS, ES+): 364.2 (M+1), LC 1: 1.86 min.

[0268] Step B:9-fluoro-2-(2-hydroxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0269] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(2-hydroxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E. Massspectrum (LC-MS, ES+): 346.1 (M+1), LC 1: 3.16 min. ¹H NMR (DMSO-d₆, 500MHz): δ 12.75 (brs, 1H); 11.8 (s, 1H); 10.06 (d, J=12.2 Hz, 1H); 8.66(brs, 1H); 8.22 (d, J=6.8 z, 2H); 7.66 (brs, 2H); 7.41 (t, J=8.5 Hz,1H); 7.29 (brs, 1H); 7.09 (m, 2H).

EXAMPLE 239-fluoro-2-(3-hydroxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0270]

[0271] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(3-hydroxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0272] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 3-hydroxybenzaldehyde).

[0273] Mass spectrum (LC-MS, ES+): 364.2 (M+1), LC 1: 1.53 min.

[0274] Step B:9-fluoro-2-(3-hydroxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0275] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(3-hydroxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0276] Mass spectrum (LC-MS, ES+): 346.2 (M+1), LC 1: 1.94 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.7 (brs, 1H); 10.05 (brs, 1H); 9.8 (s, 1H); 8.63(m, 1H); 7.72 (s, 2H); 7.60 (brs, 2H); 7.37 (t, J=8.5 Hz, 1H); 7.35(brs, 1H); 6.92 (d, J=7.1 Hz, 1H).

EXAMPLE 249-fluoro-2-(4-hydroxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0277]

[0278] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-(4-hydroxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

[0279] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 4-hydroxybenzaldehyde).

[0280] Step B:9-fluoro-2-(4-hydroxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0281] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-(4-hydroxyphenyl)-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0282] Mass spectrum (LC-MS, ES+): 346.1 (M+1), LC 1: 1.346 min.

EXAMPLE 259-fluoro-2-[2-(trifluoromethyl)phenyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0283]

[0284] Step A:4-{4-(4-fluorophenyl)-1-hydroxy-2-[2-(trifluoromethyl)phenyl]-1H-imidazol-5-yl}pyridin-2(1H)-one

[0285] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 2-trifluoromethylbenzaldehyde).

[0286] Mass spectrum (LC-MS, ES+): 416.15 (M+1), LC 1: 2.155 min.

[0287] Step B:9-fluoro-2-[2-(trifluoromethyl)phenyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0288] The title compound was prepared from4-{4-(4-fluorophenyl)-1-hydroxy-2-[2-(trifluoromethyl)phenyl]-1H-imidazol-5-yl}pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0289] Mass spectrum (LC-MS, ES+): 398.05 (M+1), LC 1: 1.864 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 11.72 (brs, 1H); 10.09 (d,J=13.5 Hz, 1H); 8.47 (t, J=7.0 Hz, 1H); 8.00 (d, J=7.8 Hz, 1H);7.95-7.54 (m, 6H); 7.28 (d, J=6.2 Hz, 1H).

EXAMPLE 262-(2-chloro-4-hydroxyphenyl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0290]

[0291] Step A:4-[2-(2-chloro-4-hydroxyphenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0292] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with2-chloro-4-hydroxy-benzaldehyde).

[0293] Mass spectrum (LC-MS, ES+): 398.05 (M+1), LC 1: 1.264 min.

[0294] Step B:2-(2-Chloro-4-hydroxy-phenyl)-9-fluoro-3,6-dihydro-7H-benz[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0295] The title compound was prepared from4-[2-(2-chloro-4-hydroxy-phenyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0296] Mass spectrum (LC-MS, ES+): 380 (M+1), LC 1: 1.876 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.7 (brs, 1H); 10.05 (brs, 1H); 8.55 (s, 1H);7.70 (d, J=8.5 Hz, 1H); 7.59 (s, 2H); 7.28 (brs, 1H); 7.04 (d, J=2.3 Hz,1H); 6.94 (dd, J₁=8.5 Hz, J₂=2.3 Hz, 1H).

EXAMPLE 272-cyclopentyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0297]

[0298] Step A:4-[2-cyclopentyl-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0299] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with cyclopentyl methanal).

[0300] Mass spectrum (LC-MS, ES+): 340.1 (M+1), LC 1: 1.688 min.

[0301] Step B:2-cyclopentyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0302] The title compound was prepared from4-[2-cyclopentyl-4-(4-fluoro-phenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0303] Mass spectrum (LC-MS, ES+): 322.1 (M+1), LC 1: 1.348 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 13.1 (s, 1H); 11.6 (brs,1H); 10.05 (dd, J₁=14.0 Hz, J₂=2.5 Hz, 1H); 8.42 (dd, J₁=8.7 Hz, J₂=6.1Hz, 1H); 7.50 (m, 2H); 7.24 (d, J=6.6 Hz, 1H); 3.40 (m, 1H); 2.14 (m,2H); 2.00 (m, 2H); 1.82 (m, 2H); 1.70 (m, 2H).

EXAMPLE 282-(Propyl)-9-fluoro-3,6-dihydro-7H-benz[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0304]

[0305] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-propyl-1H-imidazol-5-yl]pyridin-2(1H)-one

[0306] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with butyraldehyde).

[0307] Mass spectrum (LC-MS, ES+): 314.15 (M+1), LC 1: 1.081 min.

[0308] Step B:2-(Propyl)-9-fluoro-3,6-dihydro-7H-benz[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0309] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-propyl-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0310] Mass spectrum (LC-MS, ES+): 296.15 (M+1), LC 1: 1.238 min. ¹H NMR(DMSO-d₆, 500 MHz) of the major tautomer: δ 13.2 (s, 1H); 11.6 (brs,1H); 10.05 (d, J=14.2 Hz); 8.37 (m, 1H); 7.52 (m, 2H); 7.23 (d, J=6.7Hz, 1H); 2.92 (m, 2H); 1.87 (m, 2H); 0.99 (t, J=7.3 Hz, 3H).

EXAMPLE 292-(3-chlorothien-2-yl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0311]

[0312] Step A:4-[2-(3-chlorothien-2-yl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0313] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(EXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with3-chlorothiophene-2-carbaldehyde).

[0314] Mass spectrum (LC-MS, ES+): 387.95 (M+1), LC 1: 1.592 min.

[0315] Step B:2-(3-chlorothien-2-yl)-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0316] The title compound was prepared from4-[2-(3-chlorothien-2-yl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0317] Mass spectrum (LC-MS, ES+): 369.95 (M+1), LC 1: 2.048 min.

EXAMPLE 309-fluoro-2-pyridin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0318]

[0319] Step A:4-[4-(4-fluorophenyl)-1-hydroxy-2-pyridin-3-yl-1H-imidazol-5-yl]pyridin-2(1H)-one

[0320] The title compound was prepared from1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oximeEXAMPLE 1, Step B) following the procedure described in EXAMPLE 1, StepC (replacing trimethylacetaldehyde with 3-pyridinecarboxaldehyde).

[0321] Mass spectrum (LC-MS, ES+): 349.1 (M+1), LC 1: 1.13 min.

[0322] Step B:9-fluoro-2-pyridin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0323] The title compound was prepared from4-[4-(4-fluorophenyl)-1-hydroxy-2-pyridin-3-yl-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step A following the procedure described in EXAMPLE 1, Step E.

[0324] Mass spectrum (LC-MS, ES+): 331.1 (M+1), LC 1: 1.29 min. ¹H NMR(DMSO-d₆, 500 MHz): δ 11.75 (brs, 1H); 11.05 (d, J=13.8 Hz, 1H); 9.46(s, 1H); 8.69 (d, J=3.9 Hz, 1H); 8.60 (m, 2H); 7.63 (m, 3H); 7.35 (d,J=6.9 Hz, 1H).

EXAMPLE 319-Fluoro-1-methyl-2-phenyl-1,6-dihydro-7H-benz[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0325]

[0326] Step A:4-[5-(4-fluorophenyl)-1-methyl-3-oxido-2-phenyl-1H-imidazol-4-yl]pyridin-2(1H)-one

[0327] To a suspension of1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime(Example 1, Step B) (400 mg, 1.52 mmol) in acetic acid (7.6 mL) wasadded benzaldehyde (170 μL, 1.68 mmol) followed by methylamine (144 μL,40 wt. % in H₂O, 1.68 mmol), and the mixture was heated for 41 hours at100° C. It was cooled and acetic acid was removed in vacuo. The residuewas taken up in H₂O and was concentrated in vacuo two times. This wasrepeated with toluene to obtain crude residue. The crude residue wasdissolved in a mixture of CH₂Cl₂/MeOH, filtered off solid (unreacted,hydrolyzed imidazole), and the solvent was removed in vacuo. The crudeproduct was pre-absorbed on silica gel and purified by flashchromatography eluting with 5% MeOH/CH₂Cl₂ followed by 10% 2M NH₃ inMeOH/CH₂Cl₂ to obtain 270 mg of the title compound.

[0328]¹H NMR (DMSO-d₆, 500 MHz): δ 7.89 (d, J=8.3 Hz, 2H); 7.60-7.52(aromatic H's, 5H); 7.40 (t, J=8.9 Hz, 2H); 7.23 (d, J=6.9 Hz, 1H); 6.72(d, J=1.2 Hz, 1H); 6.22 (dd, J₁=7.0 Hz, J₂=1.7 Hz, 1H); 3.39 (s, 3H).MS(ES) 362 (M+1); LC 1: 1.33 min.

[0329] Step B:4-[5-(4-fluorophenyl)-1-methyl-2-phenyl-1H-imidazol-4-yl]pyridin-2(1H)-one

[0330] To a solution of4-[5-(4-fluorophenyl)-1-methyl-3-oxido-2-phenyl-1H-imidazol-4-yl]pyridin-2(1H)-oneof Step A (56 mg, 0.155 mmol) in CHCl₃ (2 mL) was added phosphoroustrichloride (16 μL, 0.186 mmol) dropwise at room temperature. Thereaction mixture was heated at 60° C. for 2 hours, cooled, and pouredinto 1N NaOH/ice solution. The aqueous layer was extracted with CH₂Cl₂,and the combined organic extracts were washed with H₂O followed bybrine. After drying over Na₂SO₄, the solvent was removed in vacuo. Thecrude material was purified by preparative thin layer chromatography(1:10 MeOH:CH₂Cl₂ as an eluent) to obtain 21.8 mg of the title compound.

[0331]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.26 (s, NH); 7.75 (d, J=7.1 Hz,2H); 7.50 (m, 5H); 7.42 (t, J=8.9 Hz, 2H); 7.20 (d, J=7.3 Hz, 1H); 6.26(m, 2H); 3.42 (s, 3H). MS(ES) 346.1 (M+1); LC 1: 1.38 min.

[0332] Step C:9-Fluoro-1-methyl-2-phenyl-1,6-dihydro-7H-benz[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0333] The title compound was prepared from4-[5-(4-fluorophenyl)-1-methyl-2-phenyl-1H-imidazol-4-yl]pyridin-2(1H)-oneof Step B according to the procedure described in EXAMPLE 1, Step E.

[0334]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.73 (brs, NH); 10.26 (dd, J₁=14 Hz,J₂=2.8 Hz, 1H); 8.68 (dd, J₁=9.1 Hz, J₂=6.1 Hz, 1H); 7.85 (d, J=6.4 Hz,2H); 7.61 (m, 5H); 7.36 (d, J=6.8 Hz, 1H); 4.27 (s, 3H). MS(ES) 344.1(M+1); LC 1: 1.73 min.

EXAMPLE 321-ethyl-9-fluoro-2-phenyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0335]

[0336] The title compound was prepared from ethylamine (70 wt. % in H₂O)according to the procedures described in EXAMPLE 31.

[0337]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.74 (brs, NH); 10.30 (dd, J₁=14 Hz,J₂=2.5 Hz, 1H); 8.53 (dd, J₁=9.0 Hz, J₂=6.0 Hz, 1H); 7.77 (d, J=6.5 Hz,2H); 7.62 (m, 5H); 7.35 (d, J=6.6 Hz, 1H); 4.66 (q, J=7.1 Hz, 3H); 1.44(t, J=7.1 Hz). MS(ES) 358.1 (M+1); LC 1: 1.86 min.

EXAMPLE 331-benzyl-9-fluoro-2-phenyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0338]

[0339] The title compound was prepared from benzylamine according to theprocedures described in EXAMPLE 31.

[0340]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.78 (brs, NH); 10.23 (dd, J₁=14 Hz,J₂=2.6 Hz, 1H); 8.16 (dd, J₁=9.0 Hz, J₂=6.3 Hz, 1H); 7.71-7.25 (11aromatic H's); 7.09 (d, J=7.7 Hz, 1H); 5.94 (s, 2H). MS(ES) 420.1 (M+1);LC 1: 2.32 min.

EXAMPLE 341-[2-(dimethylamino)ethyl]-9-fluoro-2-phenyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0341]

[0342] The title compound was prepared from N,N-dimethylethylenedianineaccording to the procedures described in EXAMPLE 31.

[0343]¹H NMR (CDCl₃, 500 MHZ): δ 10.21 (d, J=13.5 Hz, 1H); 8.32 (dd,J₁=9.0 Hz, J₂=6.0 Hz, 1H); 7.69 (m, 2H); 7.55 (m, 4H); 7.45 (m, 2H);4.66 (m, 2H); 2.74 (m, 2H); 2.12 (s, 6H). MS(ES) 401.2 (M+1); LC 1: 1.22min.

EXAMPLE 351-cyclopropyl-9-fluoro-2-phenyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0344]

[0345] The title compound was prepared from cyclopropylamine accordingto the procedures described in EXAMPLE 31.

[0346]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.73 (brs, NH); 10.23 (dd, J₁=14.1Hz, J₂=2.6 Hz, 1H); 9.04 (dd, J₁=9.0 Hz, J₂=6.2 Hz, 1H); 8.03 (d, J=6.9Hz, 2H); 7.6 (5 aromatic H's); 7.36 (d, J=6.8 Hz, 1H); 4.32 (m, 1H);1.26 (m, 2H); 0.6 (m, 2H). MS(ES) 370.1 (M+1); LC 1: 1.97 min.

EXAMPLE 369-fluoro-1-methyl-2-(2-methylphenyl)-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0347]

[0348] The title compound was prepared from methylamine (40 wt. % inH₂O) and 2-methylbenzaldehyde according to the procedures described inEXAMPLE 31.

[0349]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.72 (brs, NH); 10.27 (dd, J₁=14.2Hz, J₂=2.8 Hz, 1H); 8.67 (dd, J₁=9.1 Hz, J₂=6.3 Hz, 1H); 7.63-7.33 (7aromatic H's); 4.06 (s, 3H); 2.22 (s, 3H). MS(ES) 358.1 (M+1); LC 1:1.80 min.

EXAMPLE 372-(2,6-dichlorophenyl)-9-fluoro-1-methyl-1,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0350]

[0351] The title compound was prepared from methylamine (40 wt. % inH₂O) and 2,6-dichlorobenzaldehyde according to the procedures describedin EXAMPLE 31.

[0352]¹H NMR (DMSO-d₆, 500 MHZ): δ 11.78 (brs, NH); 10.28 (dd, J₁=14.0Hz, J₂=2.8 Hz, 1H); 8.69 (dd, J₁=9.2 Hz, J₂=6.2 Hz, 1H); 7.78-7.59 (5aromatic H's); 7.31 (d, J=6.9 Hz, 1H); 4.07 (s, 3H). MS(ES) 412.0 (M+1);LC 1: 2.85 min.

EXAMPLE 382-tert-butyl-9,10-dichloro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer A) and2-tert-butyl-8,9-dichloro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer B)

[0353]

[0354] Step A: N-Methoxy-N-methyl-3,4-dichlorobenzamide

[0355] To a suspension of 3,4-dichlorobenzoic acid (1.0 g, 5.24 mmol) inCH₂Cl₂ (25 mL) was added N,O-dimethylhydroxylamine hydrochloride (613mg, 6.28 mmol) followed by N-methylmorpholine (865 μL, 7.85 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28mmol) at which point the reaction mixture became homogeneous. After 2 h,the reaction mixture was diluted with EtOAc and washed with 1N HCl, H₂O,saturated NaHCO₃ solution and brine, sequentially. The organic layer wasdried over Na₂SO₄, and the removal of solvent in vacuo gave the titlecompound (1.16 g) that required no further purification.

[0356]¹H NMR (CDCl₃, 500 MHZ): δ 7.82 (d, J=1.8 Hz, 1H); 7.56 (dd,J₁=6.4 Hz, J₂=2.0 Hz, 1H); 7.48 (d, J=8.4 Hz, 1H); 3.54 (s, 3H); 3.36(s, 3H).

[0357] Step B: 1-(3,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)ethanone

[0358] The title compound was prepared fromN-methoxy-N-methyl-3,4-dichlorobenzamide of Step A according to theprocedure described in EXAMPLE 1, Step A.

[0359]¹H NMR (CDCl₃, 500 MHZ): δ 8.20 (d, J=5.1 Hz, 1H); 8.07 (d, J=2.1Hz, 1H); 7.81 (dd, J₁=8.5 Hz, J₂=2.1 Hz, 1H); 7.59 (d, J=8.4 Hz, 1H);6.84 (s, 1H); 4.29 (s, 2H). MS(ES) 283.9 (M+1); LC 1: 2.52 min.

[0360] Step C:1-(3,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oxime

[0361] The title compound was prepared from1-(3,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)ethanone of Step Baccording to the procedure described in EXAMPLE 1, Step B as a mixtureof cis and trans isomers.

[0362]¹H NMR (DMSO-d₆, 500 MHZ) of major isomer: δ 13.31 (brs, 1H); 8.35(d, J=5.1 Hz, 1H); 8.17 (d, J=2.0 Hz, 1H); 7.83 (m, 2H); 7.42 (m, 1H);7.30 (s, 1H). MS(ES) 313.1 (M+1); LC 1: 3.15 and 3.20 min.

[0363] Step D:4-[2-tert-butyl-4-(3,4-dichlorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

[0364] The title compound was prepared according to the proceduredescribed in EXAMPLE 1, Step C from1-(3,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione 2-oximeof Step C.

[0365]¹H NMR (CDCl₃, 500 MHZ): δ 7.56 (d, J=1.8 Hz, 1H); 7.29 (d, J=8.2Hz, 1H); 7.21 (dd, J₁=8.2 Hz, J₂=1.8 Hz, 1H); 7.15 (d, J=6.8 Hz, 1H);6.63 (d, J=1.1 Hz, 1H); 6.14 (dd, J₁=6.9 Hz, J₂=1.6 Hz, 1H); 1.42 (s,9H).

[0366] Step E:2-tert-butyl-9,10-dichloro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer A) and2-tert-butyl-8,9-dichloro-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer B)

[0367] The title compounds were prepared as regioisomers according tothe procedure described in EXAMPLE 1, Step E from4-[2-tert-butyl-4-(3,4-dichloro-phenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-oneof Step D.

[0368]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer of A: δ 12.98 (s,1H); 11.75 (brd, J=6.2 Hz, 1H); 10.55 (s, 1H); 8.84 (s, 1H); 7.56 (m,1H); 7.27 (d, J=6.7 Hz, 1H); 1.5 (s, 9H). MS(ES) 360.2 (M+1); LC 1: 2.48min.

[0369]¹H NMR (DMSO-d₆, 500 MHz) of B: δ 11.57 (brd, J=4.8 Hz, 1H); 8.45(d, J=8.7 Hz, 1H); 7.86 (d, J=8.5 Hz, 1H); 7.60 (d, J=6.4 Hz, 1H); 7.16(d, J=6.6 Hz, 1H); 1.5 (s, 9H). MS(ES) 360.1 (M+1); LC 1: 2.13 min.

EXAMPLE 399,10-dichloro-2-(2,6-dichlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer A) and8,9-dichloro-2-(2,6-dichlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one(isomer B)

[0370]

[0371] The title compounds were prepared according to the proceduresdescribed in EXAMPLE 38 using 2,6-dichlorobenzaldehyde in Step D.

[0372]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer of A: δ 11.89(brd, J=4.2 Hz, 1H); 10.61 (s, 1H); 8.61 (s, 1H); 7.78-7.62 (m, 4H);7.30 (d, J=6.6 Hz, 1H). MS(ES) 450 (M+1); LC 1: 3.0 min.

[0373]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer of B: δ 11.62(brs, 1H); 8.23 (d, J=8.3 Hz, 1H); 7.91 (d, J=8.9 Hz, 1H); 7.76-7.60 (m,4H); 7.11 (d, J=6.7 Hz, 1H). MS(ES) 450 (M+1); LC 1: 2.6 min.

EXAMPLE 402-tert-butyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0374]

[0375] The title compound was prepared according to the proceduresdescribed in EXAMPLE 38 from benzoic acid.

[0376]¹H NMR (DMSO-d₆, 500 MHz) of the major tautomer: δ 12.82 (s, 1H);11.50 (brs, 1H); 10.25 (d, J=8.7 Hz, 1H); 8.51 (d, J=8.9 Hz, 1H);7.68-7.47 (m, 3H); 7.26 (d, J=6.6 Hz, 1H); 1.51 (s, 9H). MS(ES) 292.2(M+1); LC 1: 1.79 min.

EXAMPLE 413-methyl-2-piperidin-4-yl-10-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0377]

[0378] Step A: N-benzyloxycarbonyl piperidine-4-carboxylic acid

[0379] To a cooled (0° C.) and stirred solution ofpiperidine-4-carboxylic acid (68.64 g, 0.53 mol) in water (100 mL) andTMF (200 mL) containing sodium hydroxide (23.4 g, 0.58 mol) were addeddropwise, simultaneously, benzyl chloroformate (10 g, 0.58 mol) and asolution of sodium hydroxide (23.4, 0.58 mol) in 100 mL water, over 20min. The reaction mixture was then stirred for 30 min and diluted withethyl acetate (250 mL), shaken and the organic layer discarded. The pHof the aqueous phase was adjusted to 1 with 3M HCl and extracted withmethylene chloride (3×200 mL). The combined extracts were dried oversodium sulfate and the solvent evaporated in vacuo. Ether (50 mL) andhexane (50 mL) were added and the solvent slowly evaporated in vacuogiving a solid which was triturated with 20% ether/hexane and filteredto afford a white solid 136.5 g 98%.

[0380] M.P. 73-74° C.

[0381] NMR (300 MHz, CDCl₃) δ: 7.2-7.4 (m, 5H); 5.12 (s, 2H); 4.09 (brd,2H); 2.96 (brt, 2H); 2.52 (m, 1H); 1.93 (m, 2H); 1.69 (m, 2H).

[0382] Step B: N-methyl-N-methoxy1-benzyloxycarbonylpiperidin-4-carboxamide.

[0383] To a stirred and cooled (−5° C.) solution of N-benzyloxycarbonyl4-piperidinecarboxylic acid (133.4 g, 0.51 mol) in methylene chloride(1000 mL) was added DMF (0.5 mL, catalytic), followed by dropwiseaddition of oxalyl chloride (50 mL, 0.57 mol) over 30 min. The reactionmixture was then allowed to warm to room temperature over 3 h, thevolatiles evaporated in vacuo and the residue azeotroped with methylenechloride (2×). The crude acid chloride thus obtained was dissolved inmethylene chloride (1300 mL) and the solution cooled to 0° C. beforeaddition of N,O-dimethylhydroxylamine hydrochloride (59.7 g, 0.61 mol).Triethylamine (180 mL, 1.29 mol) was added dropwise over 1 h, and thereaction allowed to warm to room temperature over 2 h. The mixture waspoured into 10% citric acid solution (750 mL) and ether (2000 mL) andthe phases separated. The organic phase was washed with water, saturatedaqueous NaHCO₃ and brine, the aqueous phases back extracted with etherand the combined organic extracts dried over sodium sulfate and thesolvent evaporated in vacuo. The product was obtained as a pale yellowoil, yield 157.5 g (quantitative yield). The material obtained was usedwithout further purification in the next step.

[0384] Step C: N-benzyloxycarbonyl piperidin-4-carboxaldehyde.

[0385] N-Methyl-N-methoxy 1-benzyloxycarbonylpiperidin-4-carboxamide(79.9 g, 261 mmol) was azeotroped with toluene (2×200 mL) to remove anywater and dissolved in THF (700 mL). The solution was cooled to −60° C.,before dropwise addition of a solution of lithium aluminum hydride inTBF (1 M, 100 mL, 100 mmol). The temperature of the reaction mixture wasallowed to rise slowly to −30° C. over approx. 1 h. The mixture wastransferred by cannula into a rapidly stirred mixture of ethyl acetate(200 mL) and 10% aqueous citric acid (500 mL), cooled to 0° C. Afteraddition was complete, ether (500 mL) was added and the phasesseparated. The organic layer was washed with 1M HCl, water, saturatedsodium bicarbonate solution and brine. After drying over anhydroussodium sulfate, the solvent was evaporated in vacuo to afford the crudeproduct, used without further purification (59 g).

[0386] NMR (300 MHz, CDCl₃) δ: 9.66 (s, 1H); 7.2-7.4 (m, 5H); 5.13 (s,2H); 4.0-4.15 (m, 2H); 3.0 (m, 2H); 2.4 (m, 1H); 1.9 (m, 2H); 1.6 (m,2H).

[0387] Step D: N-methyl-N-methoxy (3-trifluoromethyl)phenylcarboxamide.

[0388] To a suspension of N,O-dimethylhydroxylamine hydrochloride (58.2g, 0.60 mol) in dichloromethane (1 L) at 0° C., under argon, was added3-trifluoro-methylbenzoyl chloride (104.0 g, 0.50 mol) followed by aslow addition (≦+5° C.) of triethylamine (152.3 mL, 1.09 mol). Thereaction was aged for 30 min. at +5° C. and then allowed to warm to roomtemperature. TLC (1:1, ethyl acetate/hexane) showed the reaction to becomplete. The reaction was then washed with 5% aqueous citric acid (500mL) and 5% aqueous sodium bicarbonate. The aqueous extracts were backextracted with methylene chloride (100 mL) and the combined methylenechloride extracts dried over sodium sulfate, filtered and concentratedto an oil. The oil was redissolved in toluene (2×100 mL) and evaporatedin vacuo to afford the title amide (114.7 g, 98%).

[0389] NMR (300 MHz, CDCl₃) δ: 7.98 (s, 1H); 7.89 (d, J=7.8 Hz, 1H);7.72 (d, J=7.8 Hz, 1H); 7.55 (t, J=7.8 Hz, 1H); 3.55 (s, 3H); 3.39 (s,3H).

[0390] Step E:2-(2-fluoropyridin-4-yl)-1-[3-(trifluoromethyl)phenyl]ethanone.

[0391] To a stirring solution of diisopropylamine (17.69 mL, 0.135 mol)in anhydrous THP (200 mL) at −78° C., under argon, was addedn-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mol), followed after 5min. by a solution of 2-fluoro-4-methyl-pyridine (10 g, 0.090 mol) inanhydrous THF (20 mL). After stirring for 15 min. at −78° C., a solutionof N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mol) inanhydrous THF (10 mL) was added to the reaction mixture which was thenstirred for 5 min., and allowed to warm to 0° C. The reaction wasquenched with water (400 mL), and extracted with ethyl acetate (3×200mL). The ethyl acetate extracts were combined, dried over anhydroussodium sulfate, filtered, and concentrated to an oil which waschromatographed on silica gel (1 kg), eluting with 20% ethyl acetate inhexane to give 21.6 g (85%) of the title compound.

[0392]¹H NMR (300 MHz, CDCl₃) δ: 8.25(1H, s); 8.20(1H, d, J 5.1 Hz);8.18(1H, d, J 9.3 Hz); 7.88(1H, d, J 7.8 Hz); 7.67(1H, t, J 7.8 Hz);7.09(1H, d, J 5.1 Hz); 6.86(1H, s); 4.37(2H, s).

[0393] Step F:1-(2-fluoropyridin-4-yl)-2-[3-(trifluoromethyl)phenyl]ethane-1,2-dione1-oxime.

[0394] To a mixture of2-(2-fluoropyridin-4-yl)-1-[3-(trifluoromethyl)-phenyl]ethanone (10.80g, 0.038 mol) in ethanol (200 mL), at −10° C., under argon, was addedtert-butylnitrite (5.0 mL, 0.042 mol) and hydrochloric acid (12.2 mL,2.5M in ethanol, 0.031 mol) dropwise while maintaining the temperaturebelow −5° C. Upon completion of additions, the reaction was allowed towarm to RT for 2 h. The reaction was concentrated iii vacuo, dilutedwith water (100 mL), basified with saturated sodium bicarbonate (200ml). This mixture was then extracted with ethyl acetate (3×400 mL). Theorganic layers were combined, washed with water (300 mL), dried withbrine (300 mL) and anhydrous sodium sulfate, filtered and concentratedto an oil which weighed 11.4 g (96%).

[0395]¹H NMR (300 MHz, CDCl₃) δ: 8.31 (1H, s); 8.29 (1H, d, J 5.3 Hz);8.24 (1H, d, J 7.8 Hz); 7.92 (1H, d, J 8.1 Hz); 7.71 (1H, t, J 7.8 Hz);7.40 (1H, d, J 5.1 Hz); 7.23 (1H, s).

[0396] Step G:2-amino-2-(2-fluoropyridin-4-yl)-1-[3-(trifluoromethyl)phenyl]ethanol

[0397] 10% Palladium on carbon (3.0 g) was added to a solution of1-(2-fluoropyridin-4-yl)-2-[3-(trifluoromethyl)phenyl]ethane-1,2-dione1-oxime (8.0 g, 27 mmol) in ethanol (400 mL) at ambient temperature. Thereaction vessel was vacuum purged with hydrogen and vigorously stirredfor 10 hrs. After the reaction was complete, the solution was filteredthrough a pad of celite, and concentrated to give a yellow solid. Theresidue could be purified by recrystalization from methylene chlorideand hexane. Alternatively, non polar impurities could be removed byfiltration though silica gel starting with 5% methanol in methylenechloride to 5% methanol, 0.5% ammonium hydroxide in methylene chloride.Colorless solid (91%):

[0398] mp 128-129° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.01 (d, J=5.0 Hz, 1H,Ar), 7.53 (m, 1H, Ar), 7.49 (m, 2H, Ar), 7.43 (s, 1H, Ar), 7.06 (d,J=5.0 Hz, 1H, Ar), 6.86 (s, 1H, Ar), 4.96 (d, J=5.0 Hz, 1H, CH), 4.12(d, J=5.0 Hz, 1H, CH).

[0399] Step H:2-(2-fluoropyridin-4-yl)-2-(methylamino)-1-[3-(trifluoromethyl)phenyl]-ethanol

[0400]2-amino-2-(2-fluoropyridin-4-yl)-1-[3-(trifluoromethyl)phenyl]ethanol (6g, 20 mmol) was dissolved in ethyl formate (80 mL) and heated to refluxfor 10 hrs under an argon atmosphere. The reaction mixture was cooled toambient temperature and concentrated to yield (99% pure by HPLC) theformamide. Colorless oil: ¹H NMR (300 MHz, CD₃OD) δ 8.06 (m, 2H, Ar),7.55 (m, 3H, Ar), 7.05 (m, 1H, Ar), 5.22 (d, J=5.7 Hz, 1H, CH), 5.10 (d,J=5.7 Hz, 1H, CH). The formamide was azeotroped with toluene (2×100 mL)to remove trace amounts of ethyl formate and water. Reduction to thedesired compound was carried out by drop-wise addition ofborane-tetrahydrofuran complex (60 mL of a 1.0 M solution in THF, 60mmol) to a solution the formylated product (20 mmol) in THF (60 mL) atambient temperature. After 1 hr, the reaction was quenched by slowaddition of the organic mixture to a vigorously stirring solution ofaqueous hydrochloric acid (2.0 M, 500 mL). Stirring was continued for 3h to assure complete dissociation of boron with product. A solution ofaqueous sodium hydroxide (10 M) was then added until a pH of 11 wasachieved. The resulting mixture was extracted with ethyl acetate (2×300mL), dried (sodium sulfate), and concentrated. The resulting residue waspurified by filtration though a pad of silica gel (using 5% methanol and0.5% ammonium hydroxide mixture in methylene chloride). Colorless solid(89%): mp 99-102° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.99 (d, J=5.1 Hz, 1H,Ar), 7.50 (m, 1H, Ar), 7.45 (m, 2H, Ar), 7.38 (s, 1H, Ar), 7.02 (m, 1H,Ar), 6.83 (s, 1H, Ar), 5.09 (d, J=4.8 Hz, 1H, CH), 3.85 (d, J=4.8 z, 1H,CH), 2.22 (s, 3H, CH₃).

[0401] Step I: benzyl4-{[{1-(2-fluoropyridinyl)-2-hydroxy-2-[3-(trifluoromethyl)phenyl]-ethyl}(methyl)amino]carbonyl}piperidine-1-carboxylate:

[0402] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.47g, 5.1 mmol) was added to a solution of2-(2-fluoropyridin-4-yl)-2-(methylamino)-1-[3-(trifluoromethyl)phenyl]ethanol(1.60 g, 5.1 mmol), N-benzyloxycarbonyl piperidin-4-carboxylic acid(1.37 g, 5.2 mmol), triethylamine (3.5 mL, 25 mmol), and1-hydroxy-7-azabenzotriazole (717 mg, 5.4 mmol) in dimethyl formamide(50 mL) at ambient temperature. After 1 hr stirring at ambienttemperature, ethyl acetate was added (200 mL) followed by aqueous citricacid (50 mL of a 10% solution). The organic layer was then washed withaqueous sodium bicarbonate (100 mL of a sat. solution) and water (3×50mL), dried (sodium sulfate), filtered, and concentrated. The cruderesidue was passed though a pad a silica gel (50% ethyl acetate inhexane) to remove minor impurities, and taken to the next step.Colorless oil (90%): ¹H NMR (300 MHz, CD₃OD) δ 8.18 (d, J=5.4 Hz, 1H,Ar), 7.75 (m, 2H, Ar), 7.56 (m, 2H, Ar), 7.40 (m, 1H, Ar), 7.33 (m, 6H,Ar), 5.89 (d, J=9.9 Hz, 1H, CH), 5.45 (d, J=9.9 Hz, 1H, CH), 5.08 (s,2H, CH₂), 4.06 (m, 1H, CH₂), 3.88 (m, 1H, CH₂), 2.77 (s, 3H, CH₃), 2.69(m, 1H, CH₂), 2.51 (m, 1H, CH₂), 1.47 (m, 2H, CH₂), 0.93 (m, 2H, CH₂).

[0403] Step J: benzyl4-{1-methyl-5-(2-oxo-1,2-dihydropyridin-4-yl)-4-[3-(trifluoromethyl)-phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate

[0404] Oxalyl chloride (0.97 mL, 11 mmol) was added to a solution ofdimethyl sulfoxide (0.98 mL, 14 mmol) in methylene chloride (50 mL) at−78° C. After 20 min. at −78° C., the product of step I (approx. 5.1mmol from previous reaction) in methylene chloride (10 mL) was added andthe reaction solution was stirred at −78° C. for 2 hrs. Triethylamine(2.3 mL, 17 mmol) was added and the cooling bath was removed. Thesolution was diluted with ethyl acetate (150 mL), washed with aqueousammonium chloride (1×75 mL) and brine (1×75 mL), dried (sodium sulfate),and concentrated. Some non-polar impurities were removed by passing theresidue through silica gel, eluting with 50% ethyl acetate in hexane.0.298 g (0.554 mmol) of the ketone was then dissolved in acetic acid (5mL), ammonium acetate (854 mg, 11.1 mmol) added and the mixture heatedto reflux for 1.5 h. The reaction mixture was cooled, poured intoice/NH4Oh and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over anhydrous sodium sulfate and thesolvent evaporated to give the crude product, purified by flash columnchromatography (95:5:0.5 DCM:MeOH:NH₄OH to give the pyridone (250 mg).:¹H NMR (300 MHz, CD₃OD) δ 7.73 (s, 1H), 7.63 (d, 1 H), 7.3-7.55 (m, 8H),6.50 (s, 1H), 6.28 (dd, 1H), 5.15 (s, 2H), 4.37 (m, 2 H), 3.61 (s, 3H),3.00 (m, 3 H), 1.99 (m, 4H, CH₂).

[0405] Step K:4-{1-methyl-2-piperidin-4-yl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-5-yl}pyridin-2(1H)-one

[0406] Benzyl4-{1-methyl-5-(2-oxo-1,2-dihydropyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate(250 mg, 0466 mmol) in isopropanol (10 mL) was hydrogenated under 1 atm.of hydrogen over 10% Pd/C (100 mg) for 18 h, filtered and concentratedto give the crude product purified by flash column chromatography(90:10:1 DCM:MeOH:NH₄OH to give the title compound (40 mg).

[0407] MS (M+1) 403.26

[0408] Step L:3-methyl-2-piperidin-4-yl-10-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-ƒ]isoquinolin-7-one

[0409] A 1 mM stock solution of4-{1-methyl-2-piperidin-4-yl-4-[3-(trifluoro-methyl)phenyl]-1H-imidazol-5-yl}pyridin-2(1H)-onein DMSO was placed in a borosilicate glass vial and photolyzed underambient temperature and atmosphere in a Rayonet photochemical reactorequipped with four 350 nm bulbs for 40 minutes. The reaction was foundto be complete at that point as assessed by RPHPLC. MS (M+1) 401.1

EXAMPLE 422-Phenyl-3,6-dihydro-7H-imidazo[4,5-ƒ]-2,9-phenanthrolin-7-one

[0410]

[0411] Step A: tert-Butyl4-[2-oxo-2-(4-pyridinyl)ethyl]-2-pyridinylcarbamate

[0412] Tert-butyl 4-methyl-2-pyridinylcarbamate (Ihle, N. C.; Krause, A.E.; J. Org. Chem., 1996, 61(14):4810-4811; 10 g, 48.0 mmol) wasdissolved in 100 mL THF and cooled to −78° C. under argon and wastreated with n-butyllithium (2.5-M in hexanes, 48.0 mL, 120 mmol) suchthat the internal temperature did not exceed −50° C. The reaction waswarmed to 20° C. for 20 min. then was recooled to −78° C. and ethylisonicotinate (10.79 mL, 72.0 mmol) was added neat and the reactionagain was warmed to 20° C. and stirred 45 minutes. The reaction wasquenched with sat. NaHCO₃ and extracted with ethyl acetate. The organicswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a red-orange oil which was purified by silica gelchromatography, eluting from 50% ethyl acetate in hexanes to 100% ethylacetate to afford 7.56 g (50%) of the titled compound as a yellow oil.

[0413]¹H NMR (300 MHz, δ, CDCl₃): 8.84, (dd, J=3.90, 1.46 Hz, 2H,Pyr-H), 8.22-8.18 (m, 1H, Pyr-H), 7.91 (brs, 1H, Pyr-H), 7.76 (dd,J=3.90, 1.46 Hz, 2H, Pyr-H), 6.85 (d, J=5.13 Hz, 1H, Pyr-H), 4.28 (s,2H, CH₂), 1.52 (s, 9H, (CH₃)₃).

[0414] Step B: tert-Butyl4-[2-phenyl-4-(4-pyridinyl)-1H-imidazol-5-yl]-2-pyridinyl-carbamate

[0415] The tert-butyl4-[2-oxo-2-(4-pyridinyl)ethyl]-2-pyridinylcarbamate (2.40 g, 7.66 mmol)was suspended in dry DMSO (20 mL) under argon and was treated withN-bromosuccinimide (NBS, 1.50 g, 8.42 mmol). At 40-60 seconds after NBSaddition, the color of the reaction went from yellow to dark brown thenbenzamidine (3.68 g, 30.66 mmol) was added in a single portion. After 90minutes, the reaction was diluted with ethyl acetate and was washed withsat. K₂CO₃, water and brine then was dried over Na₂SO₄, filtered andconcentrated under reduced pressure with ˜20 g silica gel and thenpurified by silica gel chromatography, eluting with 0.1% triethylaminein ethyl acetate. Trituration of the purest fractions from thechromatography in hot ether gave 88 mg (3%) of the titled compound as ayellow solid.

[0416] MS (EI) M/Z=414. ¹H NMR (300 MHz, δ, CD₃OD): 8.53 (d, J=5.86 Hz,2H, Pyr-H), 8.23 (d, J=5.38 Hz, 1H, Pyr-H), 8.05 (s, 2H, Pyr-H), 8.02(s, 1H, Pyr-H), 7.62 (d, J=5.62 Hz, 2H, Ph-H), 7.54-7.44 (m, 3H, Ph-H),7.17 (brs, 1H, Pyr-H), 1.50 (s, 9H, (CH₃)₃).

[0417] Step C:4-[2-Phenyl-4-(4-pyridinyl)-1H-imidazol-5-yl]-2-pyridinamine

[0418] Trifluoroacetic acid (8 mL) was added to tert-butyl4-[2-phenyl-4-(4-pyridinyl)-1H-imidazol-5-yl]-2-pyridinylcarbamate indichloromethane (10 mL) and after 42 h, the volatiles were removed underreduced pressure. The residue was diluted with ethyl acetate and waswashed with st. K₂CO₃, dried over Na₂SO₄, filtered and concentrated invacuo to give a yellow solid which was purified by silica gelchromatography, eluting with 95 CH₂Cl₂:5 CH₃OH:0.5 NH₄OH to afford the258 mg (50%) of the titled compound as a yellow solid.

[0419] Step D:4-(2-phenyl-4-pyridin-4-yl-1H-imidazol-5-yl)pyridin-2(1H)-one

[0420] The 4-[2-phenyl-4-(4-pyridinyl)-1H-imidazol-5-yl]-2-pyridinamine(86 mg, 0.27 mmol) was dissolved in 1.5 mL water containing 0.1 mL conc.Sulfuric acid and was treated with NaNO₂ (24 mg, 0.38 mmol) and stirred60 minutes. Another 7 mg NaNO₂ (0.01 mmol) was added and the reactionwas heated over a steam bath for 5 min. then was cooled to r.t. Thereaction was basified with sat. NaHCO₃ and was extracted with ethylacetate. The combined organics were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a pale yellow solid whichwas triturated in ether to give 27 mg (31%) of the title compound as apale yellow solid.

[0421] MS (EI) M/Z=315. ¹H NMR (300 MHz, δ, DMSO-d₆): 13.03 (brs, 1H,Pyr-H), 11.61 (brs, 1H, imidazole-H), 8.66 (d, J=5.13 Hz, 1H, Pyr-H),8.55 (d, J=5.19 Hz, 1H, Pyr-H), 8.08 (t, J=7.33 Hz, 2H, Pyr-H),7.57-7.32 (m, 6H, Pyr-H, Ar-H), 6.56 (s) 6.44 (s) (1H total, Pyr-H),6.32-6.30 (m) 6.16-6.00 (m) (1H total, Pyr-H).

[0422] Step E:2-phenyl-3,6-dihydro-7H-imidazo[4,5-ƒ]-2,9-phenanthrolin-7-one

[0423] A 10.6 μL sample of a 9.4 mM DMSO stock of4-(2-phenyl-4-pyridin-4-yl-1H-imidazol-5-yl)pyridin-2(1H)-one wasdiluted to 100 μL by the addition of 89.4 μL of DMSO to give a 1 mMcompound stock. This material was then placed in a borosilicate glassvial and photolyzed under ambient temperature and atmosphere in aRayonet photochemical reactor equipped with four 350 nm bulbs for 40minutes. The reaction was found to be complete at that point as assessedby RPHPLC. UV/Vis (lmax=309 nm, shoulder at 350 nm). MS (M+H) 313.

EXAMPLE 43 Benzyl4-[7-oxo-10-(trifluoromethyl)-6,7-dihydro-3H-benzo[h]imidazo[4,5-ƒ]isoquinolin-2-yl]piperidine-1-carboxylate

[0424]

[0425] Step A: benzyl4-{5-(2-oxo-1,2-dihydropyridin-4-yl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate

[0426] A mixture of the1-(2-fluoropyridin-4-yl)-2-(3-trifluoromethylphenyl)-ethane-1,2-dione1-oxime (EXAMPLE 41, Step F) (7.3 g, 23.3 mmol), N-benzyloxy-carbonylpiperidin-4-carboxaldehyde (6.36 g, 25.7 mmol) and ammonium acetate (27g, 350 mmol) in acetic acid (100 mL) was heated to reflux for 6 h. Thereaction mixture was cooled, poured into ice/NH₄OH and extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous sodium sulfate and the solvent evaporated to give thecrude product. 400 mg of this crude product was dissolved in methanol (5mL) and TiCl₃ (3 mL of 10% solution in 20% HCl) added. Reaction mixturestirred for 30 min at room temperature then saturated aqueous sodiumbicarbonate solution added carefully and the mixture stirred vigorouslyuntil a white precipitate had formed. The solution was then partitionedwith EtOAc and the organic layer washed with water and brine, dired oversodium sulfate and the solvent evaporated. The crude product waspurified by flash column chromatography on silica (33-50% EtOAc hexane)to give the title compound (210 mg).

[0427] CHN Calc. C, 64.36%; H, 4.82%; N, 10.72%; Found C, 64.29%; H,4.82%; N, 10.57%.

[0428] Step B: Benzyl4-[7-oxo-10-(trifluoromethyl)-6,7-dihydro-3H-benzo[h]imidazo-[4,5-ƒ]isoquinolin-2-yl]piperidine-1-carboxylate

[0429] A 1 mM stock solution of benzyl4-{5-(2-oxo-1,2-dihydropyridin-4-yl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylatein DMSO was placed in a borosilicate glass vial and photolyzed underambient temperature and atmosphere in a Rayonet photochemical reactorequipped with four 350 nm bulbs for 40 minutes. The reaction was foundto be complete at that point as assessed by RPHPLC.

EXAMPLE 44 Assay For Jak Family Protein Kinase Activity

[0430] Materials. Streptavidine·allophycocyanin conjugate (SA·APC) andEuropium·ecryptate (Eu·K) were from Packard Instrument Company. Eu·Kconjugated pY20 was produced as described in Cummings, R. T.; McGovern,H. M.; Zheng, S.; Park, Y. W. and Hermes, J. D. Use Of APhosphotyrosine-Antibody Pair As A General Detection Method InHomogeneous Time Resolved Fluorescence-Application To HumanImmunodeficiency Viral Protease. Analytical Biochemistry 1999, 33,79-93. Homogenous time resolved fluorescence (HTRF) measurements weremade using the Discovery instrument from Packard. T-stim CultureSupplement was from Collaborative Biomedical Research. Recombinant mouseIL2 was from Pharmingen or R & D.

[0431] Jak family kinase expression. Jak3, Tyk2 and Jak2 kinase domainswith N-terminal “Flag” affinity tags were expressed in Sf9 cells usingstandard baculovirus methods. The human Jak3 gene was provided by Dr.John J. O'Shea (NDI). The human Tyk2 gene was provided by Dr. SandraPellegrini (Insitut Pasteur). Human Jak2 kinase domain was cloned from aMOLT4 cDNA library (Clonetech).

[0432] Assay for Jak family protein kinase activity. Tyrosine kinaseactivity was measured by detection of the tyrosine phosphorylatedpeptide amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH₂ (S, hereafter)detected by homogenous time resolved fluorescence (HTRF) using aeuropium labeled antibody to phosphotyrosine (pY20). The Jak3(JH1)catalyzed phosphorylation reactions were carried out in kinase reactionbuffer (KB) (50 mM Hepes pH 7.0, 0.01 M MgCl₂, 1 mM DTT, 1 mg/ml BSA) 1μM S, and 200 pM Jak3(JH1). Reactions were run at ambient temperatureand quenched with an equal volume of quench buffer (QB) (50 mM Hepes pH7.0, 50 mM EDTA, 100 mM KF). The quenched reactions were mixed with anequal volume of 0.5 μM·SAAPC conjugate and 0.6 nM Eu·K conjugated pY20.This mixture was incubated at ambient temperature for at least 60minutes and before detection of HTRF.

[0433] Cellular proliferation assays. CTLL-2 cells (ATCC) weremaintained in 6% T-stim Culture Supplement (source of IL2) in RPMI-1640supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate, 50 μMβ-mercaptoethanol, 1.4 mM L-glutamine, 10 mM HEPES, 1 mg/ml dextrose,0.04 mM essential amino acids, 0.02 mM nonessential amino acids,penicillin and streptomycin (H10). The day before use in theproliferation assay, cells were washed and resuspended in 0.2% Tstim ata cell concentration of 5×10⁵/ml. The next day, cells were washed andplated at 0.2-1×10⁵ cells/well in a 96 well tissue culture plate(CoStar). 0.05 ng/ml mouse recombinant IL2 (Pharmingen), with or withouta test compound, or 20 ng/ml PMA (Sigma) and 1 μCi/well [³H]-thymidinewere added. After overnight culture, cells were harvested with a glassfiber Filtermat (Wallac) and a Tomtek cell harvester. Tritiumincorporation was measured by liquid scintillation counting on aTopcount scintillation counter (Packard).

What is claimed is:
 1. A compound of formula I:

wherein one of the

bond is a double bond, and the other is a single bond; Q is N or C; R¹is attached to the nitrogen atom having the available valence, and isselected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,aryl-C₁₋₃alkyl, and aryl wherein said alkyl, alkenyl, cycloalkyl, andaryl are optionally substituted with one to three groups independentlyselected from X; R² is a group selected from R¹; R³, R⁴, R⁶ and R⁷ areindependently selected from hydrogen, X, C₂₋₆alkenyl and C₃₋₆cycloalkylwherein said alkenyl and cycloalkyl are optionally substituted with oneto three groups independently selected from X; R⁵ is selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, Cy, and Cy-C1-3alkyl, wherein saidalkyl, alkenyl, and Cy are optionally substituted with one to threegroups independently selected from X; Cy is selected from cycloalkyl,heterocyclyl, aryl, and heteroaryl; X is selected from: (a) halo, (b)CN, (c) OR^(a), (d) C₁₋₆perfluoroalkyl, (e) C(O)R^(a), (f) C(O)OR^(a),(g) C(O)NR^(b)R^(c), (h) NR^(b)R^(c), (i) NHR^(b)NHR^(b), (j)NHC(O)R^(a), (k) NHC(O)OR^(a), (l) phenyl wherein phenyl is optionallysubstituted with one to three groups independently selected from R^(x),(m) C₁₋₆alkyl optionally substituted with OH, C₃₋₇cycloalkyl, phenyl, orheterocyclyl, wherein phenyl is optionally substituted with one to threegroups independently selected from R^(x), and wherein said heterocyclylis optionally substituted with one to three groups independentlyselected from R^(y), (n) heterocyclyl wherein said heterocyclyl isoptionally substituted with one to three groups independently selectedfrom R^(y), (o) S(O)_(n)R^(a), wherein n is 0, 1 or 2 and (p)SO₂NHR^(a); R^(a), R^(b) and R^(c) are independently selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, Cy and Cy-C₁₋₃alkyl,wherein Cy is optionally substituted with one to three groups selectedfrom R^(y); or R^(b) and R^(c) together with the atom(s) to which theyare attached form a heterocyclic ring of 4 to 7 members containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(e); R^(e) is selected from hydrogen, C₁₋₆alkyl, Cy andCy-C₁₋₃alkyl; R^(x) is selected from halo, phenyl, CN, NO₂, OH,OC₁₋₆alkyl, C₁₋₆alkyl, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, C(O)C₁₋₆alkyl,C(O)OC₁₋₆alkyl, C(O)NHC₁₋₆alkyl, C(O)N(C₁₋₆alkyl)₂, NHC(O)Cl₁₋₆alkyl;R^(y) is a group selected from R^(x), oxo, C₁₋₆alkyl substituted withC₃₋₇cycloalkyl, and C(O)OCH₂-phenyl; or a pharmaceutically acceptablesalt thereof.
 2. A compound of claim 1 wherein R¹ is selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl and aryl-C₁₋₃alkyl wherein alkyl,cycloalkyl and aryl are optionally substituted with one or two groupsindependently selected from X.
 3. A compound of claim 1 wherein R³ andR⁴ are independently selected from hydrogen, halogen andtrifluoromethyl.
 4. A compound of claim 1 wherein Q is C and one of R³and R⁴ is halogen or trifluoromethyl at the 9-position, and the other isH, halogen or trifluoromethyl.
 5. A compound of claim 1 wherein R⁵ isselected from C₁₋₆alkyl and Cy wherein each is optionally substitutedwith one to three groups independently selected from X.
 6. A compound ofclaim 1 wherein R⁵ is phenyl optionally substituted with one to threegroups independently selected from X.
 7. A compound of claim 1 wherein Qis C.
 8. A compound of claim 1 wherein Q is N.
 9. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 10. A method for the treatment of Janus proteintyrosine kinase mediated diseases in a mammal which comprisesadministering to said mammal a therapeutically effective amount of acompound of claim 1.